Benzoyl-piperazine derivatives

ABSTRACT

The invention relates to compounds of formula 
                         
wherein the substituents are described herein. The compounds may be used in the treatment of illnesses based on the glycine uptake inhibitor, such as psychoses, pain, neurodegenerative disfunction in memory and learning, schizophrenia, dementia and other diseases in which cognitive processes are impaired, such as attention deficit disorders or Alzheimer&#39;s disease.

FIELD OF THE INVENTION

The present invention relates to the treatment of CNS disorders such asschizophrenia and Alzheimer's disease. More particularly, the inventionrelates to inhibition of GlyT-1.

BACKGROUND OF THE INVENTION

Schizophrenia is a progressive and devastating neurological diseasecharacterized by episodic positive symptoms such as delusions,hallucinations, thought disorders and psychosis and persistent negativesymptoms such as flattened affect, impaired attention and socialwithdrawal, and cognitive impairments (Lewis D A and Lieberman J A,Neuron, 28:325-33, 2000). For decades research has focused on the“dopaminergic hyperactivity” hypothesis which has led to therapeuticinterventions involving blockade of the dopaminergic system (VandenbergR J and Aubrey K R., Exp. Opin. Ther. Targets, 5(4): 507-518, 2001;Nakazato A and Okuyama S, et al., Exp. Opin. Ther. Patents, 10(1):75-98, 2000). This pharmacological approach poorly address negative andcognitive symptoms which are the best predictors of functional outcome(Sharma T., Br. J. Psychiatry, 174(suppl. 28): 44-51, 1999).

A complementary model of schizophrenia was proposed in the mid-1960'based upon the psychotomimetic action caused by the blockade of theglutamate system by compounds like phencyclidine (PCP) and relatedagents (ketamine) which are non-competitive NMDA receptor antagonists.Interestingly in healthy volunteers, PCP-induced psychotomimetic actionincorporates positive and negative symptoms as well as cognitivedysfunction, thus closely resembling schizophrenia in patients (Javitt DC et al., Biol. Psychiatry, 45: 668-679, 1999). Furthermore transgenicmice expressing reduced levels of the NMDAR1 subunit displays behavioralabnormalities similar to those observed in pharmacologically inducedmodels of schizophrenia, supporting a model in which reduced NMDAreceptor activity results in schizophrenia-like behavior (Mohn A R etal., Cell, 98: 427-236, 1999).

Glutamate neurotransmission, in particular NMDA receptor activity, playsa critical role in synaptic plasticity, learning and memory, such as theNMDA receptors appears to serve as a graded switch for gating thethreshold of synaptic plasticity and memory formation (Wiley, N Y; BlissT V and Collingridge G L, Nature, 361: 31-39, 1993). Transgenic miceover expressing the NMDA NR2B subunit exhibit enhanced synapticplasticity and superior ability in learning and memory (Tang J P et al.,Nature, 401-63-69, 1999).

Thus, if a glutamate deficit is implicate in the pathophysiology ofschizophrenia, enhancing glutamate transmission, in particular via NMDAreceptor activation, would be predicted to produce both anti-psychoticand cognitive enhancing effects.

The amino acid glycine is known to have at least two important functionsin the CNS. It acts as an inhibitory amino acid, binding to strychninesensitive glycine receptors, and it also influences excitatory activity,acting as an essential co-agonist with glutamate forN-methyl-D-aspartate (NMDA) receptor function. While glutamate isreleased in an activity-dependent manner from synaptic terminals,glycine is apparently present at a more constant level and seems tomodulate/control the receptor for its response to glutamate.

One of the most effective ways to control synaptic concentrations ofneurotransmitter is to influence their re-uptake at the synapses.Neurotransmitter transporters by removing neurotransmitters from theextracellular space, can control their extracellular lifetime andthereby modulate the magnitude of the synaptic transmission (GainetdinovR R et al, Trends in Pharm. Sci., 23(8): 367-373, 2002).

Glycine transporters, which form part of the sodium and chloride familyof neurotransmitter transporters, play an important role in thetermination of post-synaptic glycinergic actions and maintenance of lowextracellular glycine concentration by re-uptake of glycine intopresynaptic nerve terminals and surrounding fine glial processes.

Two distinct glycine transporter genes have been cloned (GlyT-1 andGlyT-2) from mammalian brain, which give rise to two transporters with˜50% amino acid sequence homology. GlyT-1 presents four isoforms arisingfrom alternative splicing and alternative promoter usage (1a, 1b, 1c and1d). Only two of these isoforms have been found in rodent brain (GlyT-1aand GlyT-1b). GlyT-2 also presents some degree of heterogeneity. TwoGlyT-2 isoforms (2a and 2b) have been identified in rodent brains.GlyT-1 is known to be located in CNS and in peripheral tissues, whereasGlyT-2 is specific to the CNS. GlyT-1 has a predominantly glialdistribution and is found not only in areas corresponding to strychninesensitive glycine receptors but also outside these areas, where it hasbeen postulated to be involved in modulation of NMDA receptor function(Lopez-Corcuera B et al., Mol. Mem. Biol., 18:13-20, 2001). Thus, onestrategy to enhance NMDA receptor activity is to elevate the glycineconcentration in the local microenvironment of synaptic NMDA receptorsby inhibition of GlyT-1 transporter (Bergereon R. et al., Proc. Natl.Acad. Sci. USA, 95: 15730-15734, 1998; Chen L. et al., J. Neurophysiol.,89(2): 691-703, 2003).

Glycine transporters inhibitors are suitable for the treatment ofneurological and neuropsychiatric disorders. The majority of diseasesstates implicated are psychoses, schizophrenia (Armer R E and Miller DJ, Exp. Opin. Ther. Patents, 11 (4): 563-572, 2001), psychotic mooddisorders such as severe major depressive disorder, mood disordersassociated with psychotic disorders such as acute mania or depression,associated with bipolar disorders and mood disorders, associated withschizophrenia, (Pralong E T et al., Prog. Neurobiol., 67: 173-202,2002), autistic disorders (Carlsson M L, J. Neural Trans,. 105: 525-535,1998), cognitive disorders such as dementias, including age relateddementia and senile dementia of the Alzheimer type, memory disorders ina mammal, including a human, attention deficit disorders and pain (ArmerR E and Miller D J, Exp. Opin. Ther. Patents, 11 (4): 563-572, 2001).

Thus, increasing activation of NMDA receptors via GlyT-1 inhibition maylead to agents that treat psychosis, schizophrenia, dementia and otherdiseases in which cognitive processes are impaired, such as attentiondeficit disorders or Alzheimer's disease.

SUMMARY OF THE INVENTION

The present invention provides compounds of formula I per se, andpharmaceutically acceptable salts thereof. The invention also providescompositions containing a compound of formula I or a pharmaceuticallyacceptable salt thereof. The invention further provides treatments fordiseases related to activation of NMDA receptors via Glyt-1 inhibition,which comprises administering a therapeutically effective amount of acompound of the invention. For example, the invention provides forcontrol or prevention of illnesses such as psychoses, disfunction inmemory and learning, schizophrenia, dementia and other diseases in whichcognitive processes are impaired, such as attention deficit disorders orAlzheimer's disease. The invention further provides processes formanufacturing compounds of the invention and compositions containingthem. In one aspect, the present invention relates to compounds of thegeneral formula I

wherein

-   Ar is unsubstituted or substituted aryl or 6-membered heteroaryl    containing one, two or three nitrogen atoms, and wherein the    substituted aryl and the substituted heteroaryl groups are    substituted by one or more substituents selected from the group    consisting of hydroxy, halogen, NO₂, CN, (C₁-C₆)-alkyl,    (C₁-C₆)-alkyl substituted by halogen, (C₁-C₆)-alkyl substituted by    hydroxy, (CH₂)_(n)—(C₁-C₆)-alkoxy, (C₁-C₆)-alkoxy substituted by    halogen, NR⁷R⁸, C(O)R⁹, SO₂R¹⁰, and —C(CH₃)═NOR⁷, or are substituted    by a 5-membered aromatic heterocycle containing 1-4 heteroatoms    selected from N and O, which is optionally substituted by    (C₁-C₆)-alkyl;-   R¹ is hydrogen or (C₁-C₆)-alkyl;-   R² is hydrogen, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₁-C₆)-alkyl    substituted by halogen, (C₁-C₆)-alkyl substituted by hydroxy,    (CH₂)_(n)—(C₃-C₇)-cycloalkyl optionally substituted by    (C₁-C₆)-alkoxy or by halogen, CH(CH₃)—(C₃-C₇)-cycloalkyl,    (CH₂)_(n+1)—C(O)—R⁹, (CH₂)_(n+1)—CN, bicyclo[2.2.1]heptyl,    (CH₂)_(n+1)—O—(C₁-C₆)-alkyl, (CH₂)_(n)-heterocycloalkyl,    (CH₂)_(n)-aryl or (CH₂)_(n)-5 or 6-membered heteroaryl containing    one, two or three heteroatoms selected from the group consisting of    oxygen, sulphur or nitrogen wherein aryl, heterocycloalkyl and    heteroaryl are unsubstituted or substituted by one or more    substituents selected from the group consisting of hydroxy, halogen,    (C₁-C₆)-alkyl and (C₁-C₆)-alkoxy;-   R³, R⁴ and R⁶ are each independently hydrogen, hydroxy, halogen,    (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy or O—(C₃-C₆)-cycloalkyl;-   R⁵ is NO₂, CN, C(O)R⁹ or SO₂R¹⁰;-   R⁷ and R⁸ are each independently hydrogen or (C₁-C₆)-alkyl;-   R⁹ is hydrogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy or NR⁷R⁸;-   R¹⁰ is (C₁-C₆)-alkyl optionally substituted by halogen,    (CH₂)_(n)—(C₃-C₆)-cycloalkyl, (CH₂)_(n)—(C₃-C₆)-alkoxy,    (CH₂)_(n)-heterocycloalkyl or NR⁷R⁸;    -   n is 0, 1, or 2;

or a pharmaceutically acceptable acid addition salt thereof, with theproviso that

-   1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-(3-chlorophenyl)-piperazine,-   1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-(4-fluorophenyl)-piperazine,-   1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-[3-(trifluoromethyl)phenyl]-piperazine,-   4-(3-amino-4-nitrophenyl)-1-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-2-methyl-piperazine,-   1-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-2-methyl-4-(4-nitrophenyl)-piperazine,-   4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-2-methyl-1-(4-nitrophenyl)-piperazine,-   1-(2-chloro-4-nitrophenyl)-4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-piperazine,-   1-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-4-(2,4-dinitrophenyl)-2-methyl-piperazine,-   1-(4-chloro-2-nitrophenyl)-4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-piperazine    and-   4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-1-(2,4-dinitrophenyl)-2-methyl-piperazine    are excluded.

The compounds1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-(3-chlorophenyl)-piperazine,1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-(4-fluorophenyl)-piperazine and1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-[3-(trifluoromethyl)phenyl]-piperazineare specifically described in EP 0171636, possessing inhibiting activitytowards carbonic anhydrase which plays a determining role in manyphysiological and pathological processes.

The other excluded compounds are commercially available products.

The present invention relates to compounds of general formula I, topharmaceutical composition containing them and their use in thetreatment of neurological and neuropsychiatric disorders. It hassurprisingly been found that the compounds of general formula I are goodinhibitors of the glycine transporter 1 (GlyT-1), and that they have agood selectivity to glycine transporter 2 (GlyT-2) inhibitors.

DETAILED DESCRIPTION OF THE INVENTION

The preferred indications using the compounds of the present inventionare schizophrenia, cognitive impairment and Alzheimer's disease.

Furthermore, the invention includes all racemic mixtures, all theircorresponding enantiomers and/or optical isomers.

As used herein, the term “alkyl” denotes a saturated straight- orbranched-chain group containing from 1 to 6 carbon atoms, for example,methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, 2-butyl, t-butyl andthe like. Preferred alkyl groups are groups with 1-4 carbon atoms.

The term “alkoxy” denotes a group wherein the alkyl residues is asdefined above, and which is attached via an oxygen atom.

The term “cycloalkyl” denotes a saturated carbocyclic group containing3-7 carbon atoms.

The term “alkenyl” denotes an unsaturated straight- or branched alkylchain containing from 2 to 6 carbon atoms and having one or more doublebonds, for example methylene, ethylene, propylene, isopropylene, and thelike.

The term “halogen” denotes chlorine, iodine, fluorine and bromine.

The term “aryl” denotes a monovalent cyclic aromatic hydrocarbon radicalconsisting of one or more fused rings in which at least one ring isaromatic in nature, for example phenyl, benzyl, naphthyl, biphenyl orindanyl.

The term “6-membered heteroaryl containing one, two or three nitrogenatoms” denotes a monovalent aromatic carbocyclic radical, for examplepyridyl, pyrazinyl, pyrimidinyl, pyridazinyl or 1,3,5-triazinyl.

The term “heterocycloalkyl” denotes a non aromatic hydrocarbon radical,for example oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl.

The term “5-membered aromatic heterocycle containing 1-4 heteroatoms,selected from N and O” denotes for example 1,2,4-oxadiazolyl, oxazolyl,1,3,4-oxadiazolyl or tetrazolyl.

The term “5 or 6-membered heteroaryl containing one, two or threeheteroatoms, selected from the group consisting of oxygen, sulphur ornitrogen” denotes a monovalent aromatic carbocyclic radical, for examplepyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl,thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl orisoxazolyl.

The term “alkyl, substituted by halogen” denotes for example thefollowing groups: CF₃, CHF₂, CH₂F, CH₂CF₃, CH₂CHF₂, CH₂CH₂F, CH₂CH₂CF₃,CH₂CH₂CH₂CF₃, CH₂CH₂Cl, CH₂CF₂CF₃, CH₂CF₂CHF₂, CF₂CHFCF₃, C(CH₃)₂CF₃,CH(CH₃)CF₃ or CH(CH₂F)CH₂F.

The term “alkyl, substituted by hydroxy” denotes for example thefollowing groups: CH(OH)CH₃, CH₂CH(OH)CH₃, CH₂CH(CH₃)CH₂OH, (CH₂)₂OH,(CH₂)₃OH or CH₂C[(CH₃)]₂—CH₂OH.

The term “pharmaceutically acceptable acid addition salt” embraces saltswith inorganic and organic acids, such as hydrochloric acid, nitricacid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaricacid, maleic acid, acetic acid, succinic acid, tartaric acid,methane-sulfonic acid, p-toluenesulfonic acid and the like.

“Pharmaceutically acceptable,” such as pharmaceutically acceptablecarrier, excipient, etc., means pharmacologically acceptable andsubstantially non-toxic to the subject to which the particular compoundis administered.

The term “therapeutically effective amount” denotes an amount that iseffective to prevent, alleviate or ameliorate symptoms of disease orprolong the survival of the subject being treated.

In one embodiment, the invention provides compounds of the generalformula

wherein

-   Ar is substituted aryl or unsubstituted or substituted 6-membered    heteroaryl containing one, two or three nitrogen atoms, and wherein    the substituted aryl and the substituted heteroaryl groups are    substituted by one or more substituents selected from the group    consisting of hydroxy, halogen, NO₂, CN, (C₁-C₆)-alkyl,    (C₁-C₆)-alkyl substituted by halogen, (C₁-C₆)-alkoxy, (C₁-C₆)-alkoxy    substituted by halogen, NR⁷R⁸, C(O)R⁹ and SO₂R¹⁰;-   R¹ is hydrogen or (C₁-C₆)-alkyl;-   R² is (C₁-C₆)-alkyl, (C₁-C₆)-alkyl substituted by halogen,    (C₃-C₆)-cycloalkyl, heterocycloalkyl,    (C₁-C₆)-alkyl-(C₃-C₆)-cycloalkyl, (C₁-C₆)-alkyl-heterocycloalkyl,    (C₁-C₆)-alkyl-C(O)—R⁹, (C₁-C₆)-alkyl-CN, (C₂-C₆)-alkyl-O—R¹³,    (C₂-C₆)-alkyl-NR⁷R⁸, aryl, 6-membered heteroaryl containing one, two    or three nitrogen atoms, (C₁-C₆)-alkyl-aryl, or (C₁-C₆)-alkyl-5 or    -6-membered heteroaryl containing one, two or three heteroatoms    selected from the group consisting of oxygen, sulphur or nitrogen    wherein aryl, heterocycloalkyl and heteroaryl are unsubstituted or    substituted by one or more substituents selected from the group    consisting of hydroxy, halogen, (C₁-C₆)-alkyl and (C₁-C₆)-alkoxy;-   R³, R⁴ and R⁶ are each independently hydrogen, hydroxy, halogen, CN,    (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy or NR⁷R⁸;-   R⁵ is NO₂, CN, C(O)R⁹, SO₂R¹⁰ or NR¹¹R¹²;-   R⁷ and R⁸ are each independently hydrogen or (C₁-C₆)-alkyl;-   R⁹ is hydroxy, (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl, (C₁-C₆)-alkoxy or    NR⁷R⁸;-   R¹⁰ is (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl or NR⁷R⁸;-   R¹¹ and R¹² are each independently hydrogen, C(O)—(C₁-C₆)-alkyl, or    SO₂—(C₁-C₆)-alkyl, or form together with the N-atom to which they    are attached a 5-membered heteroaryl group, optionally substituted    by halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkyl substituted by halogen or    (C₃-C₆)-cycloalkyl;-   R¹³ is hydroxy, (C₁-C₆)-alkyl or (C₃-C₆)-cycloalkyl;    or a pharmaceutically acceptable acid addition salt thereof, with    the proviso that-   1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-(3-chlorophenyl)-piperazine,-   1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-(4-fluorophenyl)-piperazine,-   1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-[3-(trifluoromethyl)phenyl]-piperazine,-   4-(3-amino-4-nitrophenyl)-1-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-2-methyl-piperazine,-   1-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-2-methyl-4-(4-nitrophenyl)-piperazine,-   4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-2-methyl-1-(4-nitrophenyl)-piperazine,-   1-(2-chloro-4-nitrophenyl)-4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-piperazine,-   1-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-4-(2,4-dinitrophenyl)-2-methyl-piperazine,-   1-(4-chloro-2-nitrophenyl)-4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-piperazine    and-   4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-1-(2,4-dinitrophenyl)-2-methyl-piperazine    are excluded.

In another embodiment, the present invention provides compounds offormula Ia

wherein

-   R is hydrogen or halogen;-   R′ is hydrogen or halogen;-   R″ is CN, C(O)—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl substituted by halogen    or S(O)₂—(C₁-C₆)-alkyl;-   R′″ is hydrogen;-   R⁵ is S(O)₂—(C₁-C₆)-alkyl, S(O)₂NH₂ or NO₂; and-   R² is (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl,    (C₁-C₆)-alkyl-(C₃-C₆)-cycloalkyl, (C₁-C₆)-alkyl substituted by    halogen, —(CH₂)₂O—(C₁-C₆)-alkyl, benzyl or aryl, optionally    substituted by halogen;    or a pharmaceutically acceptable acid addition salt thereof, with    the exception of    1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-(3-chlorophenyl)-piperazine    and    1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-[3-(trifluoromethyl)phenyl]-piperazine.

A further embodiment of the invention provides those compounds offormula Ia, wherein

-   R is hydrogen or fluoro;-   R′ is hydrogen or fluoro;-   R″ is CN, C(O)CH₃, CF₃ or S(O)₂—CH₃;-   R′″ is hydrogen;-   R⁵ is S(O)₂—CH₃, S(O)₂NH₂ or NO₂; and-   R² is (C₁-C₆)-alkyl, —CH₂-cyclopropyl, cyclopentyl, —CH₂—CF₃,    —(CH₂)₂—O—CH₃, or is benzyl or phenyl substituted by fluoro.

Examples of such compounds are2-Fluoro-4-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile,

-   [4-(3-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone,-   1-{3-fluoro-4-[4-(2-isobutoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-phenyl}-ethanone,-   4-[4-(2-isobutoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile,-   3-fluoro-4-[4-(2-isobutoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile,-   2-fluoro-4-[4-(2-isobutoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile,-   (2-isobutoxy-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,-   [4-(2-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-(2-isobutoxy-5-methanesulfonyl-phenyl)-methanone    and-   [4-(3-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-(2-isobutoxy-5-methanesulfonyl-phenyl)-methanone.

A further embodiment of the present invention provides compounds,wherein R⁵ is S(O)₂—CH₃ and R² is CH₂-cyclopropyl. An example of suchcompound is4-[4-(2-cyclopropylmethoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-3-fluoro-benzonitrile.

Compounds of formula Ia are further those, wherein R⁵ is S(O)₂—CH₃ andR² is CH₂CF₃, for example the following compounds:

-   [4-(2-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-[5-methanesulfonyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-methanone    and-   [4-(3-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-[5-methanesulfonyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-methanone.

Compounds of formula Ia are further those, wherein R⁵ is S(O)₂—CH₃ andR² is cyclopentyl, for example the following compounds:

-   4-[4-(2-cyclopentyloxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-3-fluoro-benzonitrile    and-   4-[4-(2-cyclopentyloxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-2-fluoro-benzonitrile.

Preferred compounds of formula I of the present invention are those,wherein Ar is substituted phenyl, R² is (C₁-C₆)-alkyl and R⁵ is S(O)₂CH₃or S(O)₂CH₂CH₃.

The following specific compounds relate to this group:

-   1-{3-fluoro-4-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-phenyl}-ethanone,-   3-fluoro-4-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile,-   2-Fluoro-4-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile,-   [4-(2-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone,-   1-{3-fluoro-4-[4-(2-isobutoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-phenyl}-ethanone,-   4-[4-(2-isobutoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile,-   3-fluoro-4-[4-(2-isobutoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile,-   2-fluoro-4-[4-(2-isobutoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile,-   (2-isobutoxy-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,-   [4-(2-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-(2-isobutoxy-5-methanesulfonyl-phenyl)-methanone,-   [4-(3-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-(2-isobutoxy-5-methanesulfonyl-phenyl)-methanone,-   [4-(2-fluoro-4-methanesulfonyl-phenyl)-piperazin-1-yl]-(2-isobutoxy-5-methanesulfonyl-phenyl)-methanone,-   [4-(2-fluoro-4-methanesulfonyl-phenyl)-piperazin-1-yl]-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone,-   2,3-difluoro-4-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile,-   2,3-difluoro-4-[4-(2-isobutoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile,-   2,5-difluoro-4-[4-(2-isobutoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile,-   2,6-difluoro-4-[4-(2-isobutoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile,-   3,5-difluoro-4-[4-(2-isobutoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile,-   4-[4-(2-tert-butoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-2,3-difluoro-benzonitrile,-   5-chloro-2-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile,-   4-[4-(2-tert-butoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-2,5-difluoro-benzonitrile,-   4-[4-(2-tert-butoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-3-fluoro-benzonitrile,-   (2-tert-butoxy-5-methanesulfonyl-phenyl)-[4-(2-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,-   (2-tert-butoxy-5-methanesulfonyl-phenyl)-[4-(2,5-difluoro-4-methanesulfonyl-phenyl)-piperazin-1-yl]-methanone,-   1-(4-{4-[2-(2,2-dimethyl-propoxy)-5-methanesulfonyl-benzoyl]-piperazin-1-yl}-3-fluoro-phenyl)-ethanone,-   4-{4-[2-(2,2-dimethyl-propoxy)-5-methanesulfonyl-benzoyl]-piperazin-1-yl}-benzonitrile,-   4-{4-[2-(2,2-dimethyl-propoxy)-5-methanesulfonyl-benzoyl]-piperazin-1-yl}-3-fluoro-benzonitrile,-   4-{4-[2-(2,2-dimethyl-propoxy)-5-methanesulfonyl-benzoyl]-piperazin-1-yl}-2-fluoro-benzonitrile,-   [2-(2,2-dimethyl-propoxy)-5-methanesulfonyl-phenyl]-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,-   [2-(2,2-dimethyl-propoxy)-5-methanesulfonyl-phenyl]-[4-(2-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,-   [2-(2,2-dimethyl-propoxy)-5-methanesulfonyl-phenyl]-[4-(3-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,-   [2-(2,2-dimethyl-propoxy)-5-methanesulfonyl-phenyl]-[4-(2-fluoro-4-ethanesulfonyl-phenyl)-piperazin-1-yl]-methanone,-   rac-1-{4-[4-(2-sec-butoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-3-fluoro-phenyl}-ethanone,-   rac-4-[4-(2-sec-butoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-3-fluoro-benzonitrile,-   rac-4-[4-(2-sec-butoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-2-fluoro-benzonitrile,-   rac-(2-sec-butoxy-5-methanesulfonyl-phenyl)-[4-(2-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,-   rac-(2-sec-butoxy-5-methanesulfonyl-phenyl)-[4-(3-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,-   (2-isopropoxy-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethanesulfonyl-phenyl)-piperazin-1-yl]-methanone,-   (2-isobutoxy-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethanesulfonyl-phenyl)-piperazin-1-yl]-methanone,-   2-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-5-trifluoromethyl-benzonitrile,-   1-{2-fluoro-4-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-phenyl}-ethanone,-   [4-(3-fluoro-4-methanesulfonyl-phenyl)-piperazin-1-yl]-(2-isobutoxy-5-methanesulfonyl-phenyl)-methanone,-   1-{2-fluoro-4-[4-(2-isobutoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-phenyl}-ethanone,-   2-[4-(2-isobutoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-5-trifluoromethyl-benzonitrile,-   (5-ethanesulfonyl-2-isopropoxy-phenyl)-[4-(2-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,-   [4-(4-difluoromethyl-2-fluoro-phenyl)-piperazin-1-yl]-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone,-   [4-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone,-   3-fluoro-4-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzaldehyde,-   [4-(4-ethanesulfonyl-2-fluoro-phenyl)-piperazin-1-yl]-(2-isobutoxy-5-methanesulfonyl-phenyl)-methanone,-   rac-(2-sec-butoxy-5-methanesulfonyl-phenyl)-[4-(4-ethanesulfonyl-2-fluoro-phenyl)-piperazin-1-yl]-methanone,-   [4-(4-cyclobutanesulfonyl-2-fluoro-phenyl)-piperazin-1-yl]-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone,-   [4-(4-cyclopentanesulfonyl-2-fluoro-phenyl)-piperazin-1-yl]-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone,-   [4-(4-cyclopropanesulfonyl-2-fluoro-phenyl)-piperazin-1-yl]-(2-isobutoxy-5-methanesulfonyl-phenyl)-methanone    and-   [4-(4-cyclopropanesulfonyl-2,5-difluoro-phenyl)-piperazin-1-yl]-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone.

A further preferred group of compounds of formula I are those, whereinAr is substituted phenyl, R² is (CH₂)_(n)—(C₃-C₇)-cycloalkyl and R⁵ isS(O)₂CH₃, for example the following compounds

-   1-{4-[4-(2-cyclopropylmethoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-3-fluoro-phenyl}-ethanone,-   4-[4-(2-cyclopropylmethoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile,-   4-[4-(2-cyclopropylmethoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-3-fluoro-benzonitrile,-   4-[4-(2-cyclopropylmethoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-2-fluoro-benzonitrile,-   (2-cyclopropylmethoxy-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,-   (2-cyclopropylmethoxy-5-methanesulfonyl-phenyl)-[4-(2-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,-   (2-cyclopropylmethoxy-5-methanesulfonyl-phenyl)-[4-(3-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,-   1-{4-[4-(2-cyclopentyloxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-3-fluoro-phenyl}-ethanone,-   4-[4-(2-cyclopentyloxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile,-   4-[4-(2-cyclopentyloxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-3-fluoro-benzonitrile,-   4-[4-(2-cyclopentyloxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-2-fluoro-benzonitrile,-   (2-cyclopentyloxy-5-methanesulfonyl-phenyl)-[4-(2-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,-   (2-cyclopentyloxy-5-methanesulfonyl-phenyl)-[4-(3-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,-   (2-cyclopentyloxy-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,-   Rac-[2-(1-cyclopropyl-ethoxy)-5-methanesulfonyl-phenyl]-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,-   4-[4-(2-cyclopentyloxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-2,3-difluoro-benzonitrile,-   4-[4-(2-cyclopentyloxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-2,5-difluoro-benzonitrile,-   4-[4-(2-cyclobutylmethoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile,-   4-[4-(2-cyclobutylmethoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-2-fluoro-benzonitrile,-   4-[4-(2-cyclobutylmethoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-3-fluoro-benzonitrile,-   (2-cyclobutylmethoxy-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,-   1-{4-[4-(2-cyclobutylmethoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-3-fluoro-phenyl}-ethanone,-   2-[4-(2-cyclobutylmethoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-5-trifluoromethyl-benzonitrile,-   4-[4-(2-cyclobutylmethoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-2,3-difluoro-benzonitrile,-   4-[4-(2-cyclobutylmethoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-2,5-difluoro-benzonitrile,-   4-[4-(2-cyclobutylmethoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-3,5-difluoro-benzonitrile,-   4-[4-(2-cyclobutylmethoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-2,6-difluoro-benzonitrile,-   4-[4-(2-cyclopropylmethoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl-3,5-difluoro-benzonitrile,-   4-[4-(2-cyclopentyloxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-3,5-difluoro-benzonitrile,-   4-[4-(2-cyclopropylmethoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-2,6-difluoro-benzonitrile,-   4-[4-(2-cyclopentyloxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-2,6-difluoro-benzonitrile,-   5-chloro-2-[4-(2-cyclopropylmethoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile,-   4-[4-(2-cyclohexyloxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile,-   4-[4-(2-cyclohexyloxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-3-fluoro-benzonitrile,-   4-[4-(2-cyclohexyloxy-5methanesulfonyl-benzoyl)-piperazin-1-yl]-2-fluoro-benzonitrile,-   (2-cyclohexyloxy-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,-   (2-cyclohexyloxy-5-methanesulfonyl-phenyl)-[4-(3-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,-   (2-cyclohexyloxy-5-methanesulfonyl-phenyl)-[4-(2-fluoro-4-methanesulfonyl-phenyl)-piperazin-1-yl]-methanone,-   1-{4-[4-(2-cyclobutoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-3-fluoro-phenyl}-ethanone,-   4-[4-(2-cyclobutoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-3-fluoro-benzonitrile,-   (2-cyclobutoxy-5-methanesulfonyl-phenyl)-[4-(3-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,-   (2-cyclopentyloxy-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethanesulfonyl-phenyl)-piperazin-1-yl]-methanone,-   1-{4-[4-(2-cyclopropylmethoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-2-fluoro-phenyl}-ethanone,-   2-[4-(2-cyclopentyloxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-5-trifluoromethyl-benzonitrile,-   (2-cyclopropylmethoxy-5-methanesulfonyl-phenyl)-[4-(4-ethanesulfonyl-2-fluoro-phenyl)-piperazin-1-yl]-methanone,-   (2-cyclopentyloxy-5-methanesulfonyl-phenyl)-[4-(4-ethanesulfonyl-2-fluoro-phenyl)-piperazin-1-yl]-methanone,-   (2-cyclohexyloxy-5-methanesulfonyl-phenyl)-[4-(4-ethanesulfonyl-2-fluoro-phenyl)-piperazin-1-yl]-methanone,-   (2-cyclopentyloxy-5-methanesulfonyl-phenyl)-[4-(4-cyclopropanesulfonyl-2-fluoro-phenyl)-piperazin-1-yl]-methanone,-   (2-cyclohexyloxy-5-methanesulfonyl-phenyl)-[4-(4-cyclopropanesulfonyl-2-fluoro-phenyl)-piperazin-1-yl]-methanone,-   (2-cyclobutoxy-5-methanesulfonyl-phenyl)-[4-(4-cyclopropanesulfonyl-2-fluoro-phenyl)-piperazin-1-yl]-methanone

Preferred are further compounds, wherein Ar is substituted phenyl, R² is(C₁-C₆)-alkyl substituted by halogen and R⁵ is S(O)₂CH₃. The followingcompounds relate to this group:

-   1-(3-fluoro-4-{4-[5-methanesulfonyl-2-(2,2,2-trifluoro-ethoxy)-benzoyl]-piperazin-1-yl}-phenyl)-ethanone,-   3-fluoro-4-{4-[5-methanesulfonyl-2-(2,2,2-trifluoro-ethoxy)-benzoyl]-piperazin-1-yl}-benzonitrile,-   [4-(2-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-[5-methanesulfonyl-2-(2,2,2-tri-fluoro-ethoxy)-phenyl]-methanone,-   [4-(3-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-[5-methanesulfonyl-2-(2,2,2-tri-fluoro-ethoxy)-phenyl]-methanone,-   [4-(2-fluoro-4-methanesulfonyl-phenyl)-piperazin-1-yl]-[5-methanesulfonyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-methanone,-   3-fluoro-4-{4-[5-methanesulfonyl-2-(3,3,3-trifluoro-propoxy)-benzoyl]-piperazin-1-yl}-benzonitrile,-   [4-(3-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-[5-methanesulfonyl-2-(3,3,3-trifluoro-propoxy)-phenyl]-methanone,-   [4-(2-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-[5-methanesulfonyl-2-(3,3,3-trifluoro-propoxy)-phenyl]-methanone,-   1-(3-fluoro-4-{4-[5-methanesulfonyl-2-(3,3,3-trifluoro-propoxy)-benzoyl]-piperazin    -1-yl}-phenyl)-ethanone,-   2,5-difluoro-4-[4-(5-methanesulfonyl-2-trifluoromethoxy-benzoyl)-piperazin-1-yl]-benzonitrile,-   2,3-difluoro-4-{4-[2-(2-fluoro-1-fluoromethyl-ethoxy)-5-methanesulfonyl-benzoyl]-piperazin-1-yl}-benzonitrile,-   2-fluoro-4-{4-[5-methanesulfonyl-2-(2,2,3,3,3-pentafluoro-propoxy)-benzoyl]-piperazin-1-yl}-benzonitrile,-   [5-methanesulfonyl-2-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,-   2,3-difluoro-4-{4-[5-methanesulfonyl-2-(2,2,3,3,3-pentafluoro-propoxy)-benzoyl]-piperazin-1-yl}-benzonitrile,-   3,5-difluoro-4-{4-[5-methanesulfonyl-2-(2,2,3,3,3-pentafluoro-propoxy)-benzoyl]-piperazin-1-yl}-benzonitrile,-   2-{4-[2-(2-fluoro-1-fluoromethyl-ethoxy)-5-methanesulfonyl-benzoyl]-piperazin-1-yl}-5-trifluoromethyl-benzonitrile,-   rac-2,3-difluoro-4-{4-[5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoyl]-piperazin-1-yl}-benzonitrile,-   2-Fluoro-4-{4-[5-methanesulfonyl-2-(2,2,3,3-tetrafluoro-propoxy)-benzoyl]-piperazin-1-yl}-benzonitrile,-   3-fluoro-4-{4-[5-methanesulfonyl-2-(2,2,3,3-tetrafluoro-propoxy)-benzoyl]-piperazin-1-yl}-benzonitrile,-   [5-methanesulfonyl-2-(2,2,3,3-tetrafluoro-propoxy)-phenyl]-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,-   [4-(2-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-[5-methanesulfonyl-2-(2,2,3,3-tetrafluoro-propoxy)-phenyl]-methanone,-   2,3-difluoro-4-{4-[5-methanesulfonyl-2-(2,2,3,3-tetrafluoro-propoxy)-benzoyl]-piperazin-1-yl}-benzonitrile,-   3,5-Difluoro-4-{4-[5-methanesulfonyl-2-(2,2,3,3-tetrafluoro-propoxy)-benzoyl]-piperazin-1-yl}-benzonitrile,-   [4-(3,4-dichloro-phenyl)-piperazin-1-yl]-[5-methanesulfonyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-methanone,-   rac-5-chloro-2-{4-[5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoyl]-piperazin-1-yl}-benzonitrile,-   rac-3,5-difluoro-4-{4-[5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoyl]-piperazin-1-yl}-benzonitrile,-   rac-2,5-difluoro-4-{4-[5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoyl]-piperazin-1-yl}-benzonitrile,-   rac-2,6-difluoro-4-{4-[5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoyl]-piperazin-1-yl}-benzonitrile,-   rac-4-{4-[5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoyl]-piperazin-1-yl}-benzonitrile,-   rac-3-fluoro-4-{4-[5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoyl]-piperazin-1-yl}-benzonitrile,-   rac-2-fluoro-4-{4-[5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoyl]-piperazin-1-yl}-benzonitrile,-   rac-5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,-   rac-[4-(2-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-[5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone,-   rac-[4-(3-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-[5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone,-   [4-(2-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S    or R)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone,-   [5-methanesulfonyl-2-((S or    R)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone    and-   [5-methanesulfonyl-2-((R or    S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone.

Preferred compounds of formula I of the present invention are furtherthose wherein Ar is substituted phenyl, R² is (C₁-C₆)-alkyl,(C₁-C₆)-alkyl substituted by halogen, CH₂)_(n)—(C₃-C₇)-cycloalkyl,bicycle[2.2.1]heptyl, (CH₂)_(n)—O—(C₁-C₆)-alkyl orCH₂)_(n)-heterocycloalkyl, and R⁵ is NO₂. Examples of such compoundsinclude:

-   1-(3-fluoro-4-{4-[2-(2-methoxy-ethoxy)-5-nitro-benzoyl]-piperazin-1-yl}-phenyl)-ethanone,-   (2-isopropoxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,-   (2-cyclopropylmethoxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,-   (2-cyclobutylmethoxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,-   (2-butoxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,-   [2-(2,2-dimethyl-propoxy)-5-nitro-phenyl]-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,-   (2-isobutoxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,-   (2-cyclopentyloxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,-   (5-nitro-2-propoxy-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,-   (2-cyclobutoxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,-   Rac-(2-sec-butoxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,-   [5-nitro-2-(2,2,3,3-tetrafluoro-propoxy)-phenyl]-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,-   [5-nitro-2-(2,2,2-trifluoro-ethoxy)-phenyl]-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,-   [2-(bicyclo[2.2.1]hept-2-yloxy)-5-nitro-phenyl]-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,-   [2-(2-chloro-ethoxy)-5-nitro-phenyl]-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,    and-   [5-nitro-2-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone.

Further preferred are compounds wherein Ar is substituted phenyl, R² is(C₁-C₆)-alkyl, (C₁-C₆)-alkyl substituted by halogen or(CH₂)_(n)—(C₃-C₇)-cycloalkyl and R⁵ is S(O)₂NHCH₃. Examples of suchcompounds include

-   3-[4-(4-Cyano-3-fluoro-phenyl)-piperazine-1-carbonyl]-N-methyl-4-trifluoromethoxy-benzenesulfonamide,-   3-[4-(4-cyano-3-fluoro-phenyl)-piperazine-1-carbonyl]-4-isobutoxy-N-methyl-benzenesulfonamide,-   3-[4-(4-cyano-3-fluoro-phenyl)-piperazine-1-carbonyl]-4-cyclopentyloxy-N-methyl-benzenesulfonamide,-   3-[4-(4-cyano-3-fluoro-phenyl)-piperazine-1-carbonyl]-4-cyclobutoxy-N-methyl-benzenesulfonamide,-   3-[4-(4-cyano-3-fluoro-phenyl)-piperazine-1-carbonyl]-4-cyclobutylmethoxy-N-methyl-benzenesulfonamide,-   3-[4-(4-cyano-phenyl)-piperazine-1-carbonyl]-4-isobutoxy-N-methyl-benzenesulfonamide,-   3-[4-(4-cyano-phenyl)-piperazine-1-carbonyl]-4-cyclopentyloxy-N-methyl-benzenesulfonamide,-   3-[4-(4-cyano-phenyl)-piperazine-1-carbonyl]-4-cyclobutylmethoxy-N-methyl-benzenesulfonamide,-   3-[4-(4-cyano-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-isobutoxy-N-methyl-benzenesulfonamide,-   3-[4-(4-cyano-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-(2,2-dimethyl-propoxy)-N-methyl-benzenesulfonamide,-   3-[4-(4-cyano-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-isopropoxy-N-methyl-benzenesulfonamide,-   3-[4-(4-cyano-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-cyclopentyloxy-N-methyl-benzenesulfonamide,-   3-[4-(4-cyano-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-cyclobutoxy-N-methyl-benzenesulfonamide,-   3-[4-(4-cyano-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-cyclopropylmethoxy-N-methyl-benzenesulfonamide,-   3-[4-(4-cyano-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-cyclobutylmethoxy-N-methyl-benzenesulfonamide,-   3-[4-(4-acetyl-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-isobutoxy-N-methyl-benzenesulfonamide,-   3-[4-(4-acetyl-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-(2,2-dimethyl-propoxy)-N-methyl-benzenesulfonamide,-   3-[4-(4-acetyl-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-cyclopentyloxy-N-methyl-benzenesulfonamide,-   3-[4-(4-acetyl-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-cyclobutoxy-N-methyl-benzenesulfonamide,-   3-[4-(4-acetyl-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-cyclopropylmethoxy-N-methyl-benzenesulfonamide,-   4-isobutoxy-N-methyl-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzenesulfonamide,-   4-(2,2-dimethyl-propoxy)-N-methyl-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzenesulfonamide,-   4-isopropoxy-N-methyl-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzenesulfonamide,-   4-cyclopentyloxy-N-methyl-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzenesulfonamide,-   4-cyclobutoxy-N-methyl-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzenesulfonamide,-   4-cyclopropylmethoxy-N-methyl-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzenesulfonamide,-   4-cyclobutylmethoxy-N-methyl-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzenesulfonamide,-   N-methyl-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-4-(3,3,3-trifluoro-propoxy)-benzenesulfonamide,-   3-[4-(4-cyano-2-fluoro-phenyl)-piperazine-1-carbonyl]-N-methyl-4-(2,2,2-trifluoro-ethoxy)-benzenesulfonamide,-   N-methyl-4-(2,2,2-trifluoro-ethoxy)-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzenesulfonamide,-   rac-N-methyl-4-(2,2,2-trifluoro-1-methyl-ethoxy)-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzenesulfonamide,-   rac-3-[4-(4-cyano-2,5-difluoro-phenyl)-piperazine-1-carbonyl]-N-methyl-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonamide,    and-   rac-3-[4-(4-cyano-2,3-difluoro-phenyl)-piperazine-1-carbonyl]-N-methyl-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonamide.

A further preferred group of compounds of formula I are those wherein Aris a substituted 6-membered heteroaryl group containing one, two orthree nitrogen atoms, R² is (C₁-C₆)-alkyl orCH₂)_(n)—(C₃-C₇)-cycloalkyl, and R⁵ is SO₂CH₃. Examples of the compoundsinclude:

-   [4-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-(2-cyclopropylmethoxy-5-methanesulfonyl-phenyl)-methanone,-   6-[4-(2-cyclopentyloxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-nicotinonitrile,-   (2-cyclopentyloxy-5-methanesulfonyl-phenyl)-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone,-   [4-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-(2-cyclopentyloxy-5-methanesulfonyl-phenyl)-methanone,-   (2-cyclopentyloxy-5-methanesulfonyl-phenyl)-[4-(6-trifluoromethyl-pyridin-3-yl)-piperazin-1-yl]-methanone,-   [4-(3-fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone,    and-   (2-cyclopentyloxy-5-methanesulfonyl-phenyl)-[4-(3-fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone.

Further preferred are compounds of formula I, wherein Ar is asubstituted 6-membered heteroaryl group containing one, two or threenitrogen atoms, R² is (C₁-C₆)-alkyl substituted by halogen and R⁵ isSO₂CH₃. Examples of these compounds include:

-   rac-[4-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone,-   rac-[5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone,-   rac-[4-(5-bromo-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone,-   rac-[4-(3-fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone,-   rac-[5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-[4-(6-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone,-   [5-methanesulfonyl-2-((S or    R)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone,-   [5-methanesulfonyl-2-((R or    S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone,-   [4-(3-fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone,    and-   [4-(3-fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-phenyl]-methanone.

The present compounds of formula I and their pharmaceutically acceptablesalts can be prepared by methods known in the art, for example, byprocesses described below. One such process comprises

-   a) reacting a compound of formula

with a compound of formula

in the presence of an activating agent, such as TBTU(2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate),to produce a compound of formula

wherein the substituents are as defined above, or

-   b) reacting a compound of formula

with a compound of formulaR²OHoptionally in the presence of a catalyst, such as Cu(I)I, and a base,like potassium carbonate, cesium carbonate or sodium, to produce acompound of formula

wherein X is halogen and the other substituents are as defined above, or

-   c) reacting a compound of formula

with a compound of formulaR²Xin the presence of a base and optionally in the presence of microwavesto produce a compound of formula

wherein X is halogen, mesylate or triflate and the other substituentsare as defined above, or

-   d) reacting a compound of formula

with a compound of formulaR²OHunder Mitsunobu conditions in the presence of a phosphine to produce acompound of formula

wherein the substituents are as defined above, or

-   e) reacting a compound of formula

with a compound of formulaArXto produce a compound of formula

wherein X is halogen and the other substituents are as defined above, or

-   f) reacting a compound of formula

with a corresponding amine or alcohol in the presence of an activatingagent to produce a compound of formula

wherein R⁹ is (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl, (C₁-C₆)-alkoxy orNR⁷R⁸; and the other substituents are as defined above, or

-   g) reacting a compound of formula

with a compound of formula RONH₂ to produce a compound of formula

wherein R is H or alkyl and the other substituents are as defined above,or

-   h) reacting a compound of formula

with a reducing agent, like sodium borohydride (when R is H), or analkylating agent, like alkyllithium (when R is alkyl), to produce acompound of formula

wherein R is H or alkyl and the other substituents are as defined above,and if desired, converting the compounds obtained into pharmaceuticallyacceptable acid addition salts.

The compounds of formula I may be prepared in accordance with processvariant a) to h) and with the following schemes 1 to 8. The startingmaterials are commercially available or maybe prepared in accordancewith known methods.

Compounds of general formula I can be prepared by reacting piperazinederivatives of formula II with a corresponding acid of formula III inthe presence of an activating agent like TBTU(2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate).The acid of formula III can be prepared by reaction of an acid offormula IV with an alcohol of formula R²OH, optionally in the presenceof a copper salt like Cu(I)Br. Piperazine derivatives of formula II canbe prepared by heating of the corresponding piperazine with ArX or byreacting of a N-protected piperazine with ArX in the presence ofpalladium catalyst followed by cleavage of the protective group. Theprotective group is typically tert-butoxycarbonyl (Boc).

Alternatively, compounds of general formula I can be prepared byreaction of an acyl-piperazine of formula V and an alcohol of formulaR²OH, optionally in the presence of a copper salt like Cu(I)I.Acylpiperazine derivatives of formula V can be prepared by reaction ofan acid of formula IV with piperazine derivatives of formula II in thepresence of an activating agent like TBTU(2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate).

Compounds of general formula I can be prepared by reacting a compound offormula VI with an electrophile of formula R²X in the presence of baselike potassium carbonate and optionally in the presence of microwaves,wherein X is halogen, mesylate or triflate.

Compounds of general formula I can be prepared by reacting phenol offormula VI with an alcohol of formula R²OH under Mitsunobu conditions,in the presence of a phosphine, like triphenylphosphine ordiphenyl-2-pyridylphosphine, and a dialkylazadicarboxylate, likediethylazadicarboxylate or di-tert-butyl azodicarboxylate.

The compound of formula VI can be prepared by deprotection (for exampleusing hydrogen) of a phenol protected as a benzyl ether (I with R₂:benzyl).

Alternatively, a compound of formula VI can be prepared by reactingpiperazine derivatives of formula II with an acid of formula VII in thepresence of an activating agent like TBTU(2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate).

Compounds of general formula I can be prepared by reacting a piperazineof formula VIII with ArX.

wherein R⁹ is (C₁-C₆)-alkoxy or NR⁷R⁸;

Compounds of general formula Ib wherein R⁹ is as defined above can beprepared by reacting an acid of formula Ia with a corresponding amine oralcohol in the presence of an activating agent like carbonyldimidazole.

Compounds of general formula Id can be prepared in accordance withscheme 7 by reacting a compound of formula Ic bearing a carbonyl group,with a compound of formula RONH₂, wherein R is H or alkyl and R⁹ is(C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl, (C₁-C₆)-alkoxy or NR⁷R⁸.

Compounds of general formula Ie wherein R is H or alkyd and R⁹ is(C₁-C₆)-alkyl or (C₃-C₆)-cycloalkyl can be prepared by reacting acompound of formula Ic bearing a carbonyl group, with a reducing agentlike sodium borohydride (when R is H) or an alkylating agent likealkyllithium (when R is alkyl).

Racemic mixtures of chiral compounds of formula I can be separated usingchiral HPLC.

The acid addition salts of the basic compounds of formula I may beconverted to the corresponding free bases by treatment with at least astoichiometric equivalent of a suitable base such as sodium or potassiumhydroxide, potassium carbonate, sodium bicarbonate, ammonia, and thelike.

The following 660 examples illustrate the present invention withoutlimiting it. All temperatures are given in degree Celsius.

The following abbreviations were used in the examples:

-   RT: room temperature;-   n-Boc-piperazine: tert-Butyl 1-piperazinecarboxylate,-   oxone®: (potassium peroxymonosulfate) 2KHSO₅.KHSO₄.K₂SO₄,-   EtOAc: ethyl acetate;-   THF: tetrahydrofuran;-   TBTU:    2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate;-   DIPEA: diisopropylethylamine,-   DMF: N,N-dimetyhylformamide

EXAMPLE 1.1 Preparation of1-(2-Fluoro-4-trifluoromethyl-phenyl)-piperazine

(a) 4-(2-Fluoro-4-trifluoromethyl-phenyl)-piperazine-1-carboxylic acidtert-butyl ester

A mixture of 20 mmol 1-bromo-2-fluoro-4-trifluoromethyl-benzene, 24.7mmol n-Boc-piperazine, 0.1 mmol Tris(dibenzylideneacetone)dipalladiumchloroform complex, 28.8 mmol sodium-t-butoxide and 0.4 mmol2-(dicyclohexylphosphino)biphenyl in 50 ml toluene was heated for 16 hat 80° C. After cooling to RT the mixture was treated with 15 g IsoluteHM-N and all volatiles were removed under vacuum. The residue waspurified on silica eluting with a gradient of heptane/EtOAc to yieldafter evaporation the title compound.

(b) 1-(2-Fluoro-4-trifluoromethyl-phenyl)-piperazine

A mixture of 9 mmol4-(2-fluoro-4-trifluoromethyl-phenyl)-piperazine-1-carboxylic acidtert-butyl ester in 20 ml dioxane was treated with 8.93 ml 4N HCl indioxane for 2 h at 80° C. The mixture was concentrated and treated with20 ml water, 20 ml 2M Na₂CO₃ and extracted with 50 ml EtOAc. The organicphase was washed with 30 ml saturated NaCl. AU aqueous phases werecombined and extracted with 50 ml EtOAc. The combined organic phaseswere dried with MgSO₄ and evaporated to yield the title compound 1.1.

1-H-NMR (300 MHz, CDCl₃) δ=7.50 (d, J=13.3 Hz, 1H, H-3), 7.45 (d, J=8.8Hz, 1H, H-5), 7.16 (dd, J₁=8.8 Hz, J₂=8.8 Hz, 1H, H-6), 3.5-3.2 (s, br,1H, NH), 3.04 (m, 4H, piperazine), 2.87 (m, 4H, piperazine).

MS (m/e): 249.2 (MH⁺, 100%)

EXAMPLE 1.2 Preparation of 2-isopropoxy-5-methanesulfonyl-benzoic acid

(a) 2-Chloro-5-methanesulfonyl-benzoic acid

To 99 mmol 2-chloro-5-(methylthio) benzoic acid in 400 ml methanol at 0°C. 296 mmol oxone® was added, and the mixture was allowed to stir at RTfor 3.5 h. The precipitate was filtered off, and the filtrate wasconcentrated under reduced pressure. The residue was extracted 3× with400 ml ethyl acetate, and the combined organic phases washed 2× with 300ml 1N HCl and with 300 ml saturated aqueous NaCl solution and dried withMgSO₄. Evaporation under reduced pressure yielded the title compound.

(b) 2-Isopropoxy-5-methanesulfonyl-benzoic acid

A mixture of 2.13 mmol 2-chloro-5-methanesulfonyl-benzoic acid, 0.64mmol Cu(I)Br in 5 ml NEt₃ and 25 ml isopropanol was heated to 120° C.for 16 h in a sealed tube. The volatiles were removed under vacuum, andthe residue was taken up in 70 ml 1N HCl. Extraction with ethyl acetatedrying of the combined organic fractions and evaporation yielded aresidue which was purified by reversed phase preparative HPLC elutingwith an acetonitrile/water gradient. Evaporation of the productfractions yielded the title compound 1.2.

MS (m/e): 257.0 (MH⁻, 100%)

In analogy to Example 1.2(b) compounds 1.3 to 1.7 of the following tablewere prepared from 2-chloro-5-methanesulfonyl-benzoic acid and theappropriate alcohol:

Compound Name Alcohol MS (m/e) 1.3 2-isobutoxy-5-methanesulfonyl-isobutanol 271.1 (MH⁻, benzoic acid 100%) 1.42-cyclopropylmethoxy-5-methanesulfonyl- cyclopropyl-methanol 269.1 (MH⁻,benzoic acid 100%) 1.5 5-methanesulfonyl-2-(2,2,2-trifluoro-2,2,2-trifluoro-ethanol 297.0 (MH⁻, ethoxy)-benzoic acid 100%) 1.62-cyclopentyloxy-5-methanesulfonyl- cyclopentanol 282.9 (MH⁻, benzoicacid 100%) 1.7 2-(4-fluoro-phenoxy)-5-methanesulfonyl- 4-fluoro-phenol309.1 (MH⁻, benzoic acid (in THF) 100%)

EXAMPLE 1.8 Preparation of1-{3-fluoro-4-[4-(2-fluoro-5-nitro-benzoyl)-piperazin-1-yl]-phenyl}-ethanone

A solution of 0.261 mmol 2-fluoro-5-nitro-benzoyl chloride [CAS:7304-32-7; Feng and Burgess, Chem. Europ. J. EN, 5:3261-3272 (1999)] in1 ml dioxane was treated with 0.522 mmol triethylamine and then with asolution of 0.261 mmol 1-(3-fluoro-4-piperazin-1-yl-phenyl)-ethanone(CAS: 189763-57-3; WO 97/14,690) in 1 ml dioxane. The mixture wasstirred at RT for 30 min. The solvent was removed in vacuo. The crudeoil was taken up in water. The aqueous layer was extracted 3 times withCH₂Cl₂. The combined extracts were dried over Na₂SO₄, filtered, and thesolvent was removed in vacuo. The crude gum was purified on silica gel(eluent: heptane/ethylacetate 0%-20% (10 min) to provide the titlecompound 1.8.

MS (m/e): 390.2 (MH⁺, 100%)

EXAMPLE 1.9 Preparation of(2-iodo-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone

(a) 2-Amino-5-methanesulfonyl-benzoic acid

A mixture of 4.26 mmol 2-chloro-5-methanesulfonyl-benzoic acid, 0.39mmol Copper powder and 10 ml ammonium hydroxide 25% was heated at125-130° C. with stirring for 18 hours. Mixture was cooled to roomtemperature and filtered. The solid was washed with methanol. Thefiltrate was concentrated in vacuo. The residue was acidified with HCl1N to pH=2. The obtained solid was washed with water and dried (HV, 50°C., 1 hour) to yield the title compound MS (m/e): 214.1 (M−H, 100%)

(b) 2-Iodo-5-methanesulfonyl-benzoic acid

To a suspension of 3.0 mmol 2-amino-5-methanesulfonyl-benzoic acid in amixture of 1.7 ml sulfuric acid and 1.7 ml water was added dropwise asolution of 3.92 mmol sodium nitrite in 1.7 ml water at such rate thatthe temperature did not exceed 3° C. The mixture was stirred at 0° C.for 1 hour. A solution of 3.0 mmol KI in 1.7 ml water was added dropwiseat 0° C. The brown suspension was allowed to warm to rt and stirred for30 minutes. Excess iodine was destroyed by addition of a few drops of asodium hydrogenosulfite solution. The solid was filtered, washed withwater and dried (HV, 50° C., 1 hour) to yield the title compound. MS(m/e): 325.0 (M−H, 100%)

(c)(2-iodo-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]methanone

To a solution of 9.2 mmol 2-iodo-5-methanesulfonyl-benzoic acid in 20 mldimethylformamide 11.5 mmol TBTU, 46.0 mmol N-ethyldiisopropylamine and11.0 mmol 1-(4-trifluoromethylphenyl)piperazine (ABCR F07741NB,[30459-17-7])were successively added. The reaction was then stirred atRT for two hours, concentrated in vacuo and purified by columnchromatography (SiO₂, 50 g, CH₂Cl₂/MeOH/NH₃=100/0/0 to 95/4.5/0.5), togive the title compound 1.9. MS (m/e): 539.1 (M+H⁺)

EXAMPLE 5 Preparation of[4-(2-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone

A mixture of 0.05 mmol 2-isopropoxy-5-methanesulfonyl-benzoic acid(Compound 1.2), 0.06 mmol1-(2-fluoro-4-trifluoromethyl-phenyl)-piperazine, 0.055 mmol TBTU and0.25 mmol DIPEA in 1 ml DMF was stirred at RT for 16 h. 0.5 mlMeOH/HCOOH 1/1 was added and the mixture was subjected to reversed phasepreparative HPLC separation eluting with an acetonitrile/water gradientyielding the title compound. MS (m/e): 489.2 (MH⁺, 100%)

In analogy to Example 5 compounds 1 to 4, 6 to 46 and 52-54 of thefollowing table were prepared from the acid derivatives and piperazinederivatives:

Expl. MW found No. Systematic Name Starting materials (MH⁺) 11-{3-fluoro-4-[4-(2-isopropoxy-5- 1-(3-fluoro-4-piperazin-1-yl- 463.2methanesulfonyl-benzoyl)-piperazin- phenyl)-ethanone and Compound 1.21-yl]-phenyl}-ethanone 2 4-[4-(2-isopropoxy-5-methanesulfonyl-4-piperazin-1-yl-benzonitrile and 428.2benzoyl)-piperazin-1-yl]-benzonitrile Compound 1.2 33-fluoro-4-[4-(2-isopropoxy-5- 3-fluoro-4-piperazin-1-yl-benzonitrile446.2 methanesulfonyl-benzoyl)- and Compound 1.2piperazin-1-yl]-benzonitrile 4 2-Fluoro-4-[4-(2-isopropoxy-5-2-fluoro-4-piperazin-1-yl-benzonitrile 446.2 methanesulfonyl-benzoyl)-and Compound 1.2 piperazin-1-yl]-benzonitrile 5[4-(2-fluoro-4-trifluoromethyl- 1-(2-fluoro-4-trifluoromethyl- 489.2phenyl)-piperazin-1-yl]-(2- phenyl)-piperazine andisopropoxy-5-methanesulfonyl- Compound 1.2 phenyl)-methanone 6[4-(3-fluoro-4-trifluoromethyl- 1-(3-fluoro-4-trifluoromethyl- 489.2phenyl)-piperazin-1-yl]-(2-iso- phenyl)-piperazine andpropoxy-5-methanesulfonyl- Compound 1.2 phenyl)-methanone 71-{3-fluoro-4-[4-(2-isobutoxy-5- 1-(3-fluoro-4-piperazin-1-yl- 477.2methanesulfonyl-benzoyl)- phenyl)-ethanone and Compound 1.3piperazin-1-yl]-phenyl}-ethanone 8 4-[4-(2-isobutoxy-5-4-piperazin-1-yl-benzonitrile and 442.2 methanesulfonyl-benzoyl)-Compound 1.3 piperazin-1-yl]-benzonitrile 93-fluoro-4-[4-(2-isobutoxy-5- 3-fluoro-4-piperazin-1-yl- 460.3methanesulfonyl-benzoyl)- benzonitrile and Compound 1.3piperazin-1-yl]-benzonitrile 10 2-fluoro-4-[4-(2-isobutoxy-5-2-fluoro-4-piperazin-1-yl- 460.3 methanesulfonyl-benzoyl)- benzonitrileand Compound 1.3 piperazin-1-yl]-benzonitrile 11(2-isobutoxy-5-methanesulfonyl- 1-(4-trifluoromethyl-phenyl)- 485.3phenyl)-[4-(4-trifluoromethyl-phenyl)- piperazine and Compound 1.3piperazin-1-yl]-methanone 12 [4-(2-fluoro-4-trifluoromethyl-1-(2-fluoro-4-trifluoromethyl- 503.2phenyl)-piperazin-1-yl]-(2-isobutoxy- phenyl)-piperazine and5-methanesulfonyl-phenyl)- Compound 1.3 methanone 13[4-(3-fluoro-4-trifluoromethyl- 1-(3-fluoro-4-trifluoromethyl- 503.1phenyl)-piperazin-1-yl]-(2-isobutoxy- phenyl)-piperazine and5-methanesulfonyl-phenyl)- Compound 1.3 methanone 14[4-(2-fluoro-4-methanesulfonyl- 1-(2-fluoro-4-methanesulfonyl- 513.3phenyl)-piperazin-1-yl]-(2-isobutoxy- phenyl)-piperazine and5-methanesulfonyl-phenyl)- Compound 1.3 methanone 151-{4-[4-(2-cyclopropylmethoxy-5- 1-(3-fluoro-4-piperazin-1-yl- 475.2methanesulfonyl-benzoyl)- phenyl)-ethanone and Compound 1.4piperazin-1-yl]-3-fluoro-phenyl}- ethanone 164-[4-(2-cyclopropylmethoxy-5- 4-piperazin-1-yl-benzonitrile and 440.3methanesulfonyl-benzoyl)-piperazin- Compound 1.4 1-yl]-benzonitrile 174-[4-(2-cyclopropylmethoxy-5- 3-fluoro-4-piperazin-1-yl-benzonitrile458.3 methanesulfonyl-benzoyl)-piperazin- and Compound 1.41-yl]-3-fluoro-benzonitrile 18 4-[4-(2-cyclopropylmethoxy-5-2-fluoro-4-piperazin-1-yl-benzonitrile 458.3methanesulfonyl-benzoyl)-piperazin- and Compound 1.41-yl]-2-fluoro-benzonitrile 19 (2-cyclopropylmethoxy-5-methanesulfonyl-1-(4-trifluoromethyl-phenyl)- 483.2 phenyl)-[4-(4-trifluoromethyl-piperazine and Compound 1.4 phenyl)-piperazin-1-yl]-methanone 20(2-cyclopropylmethoxy-5-methanesulfonyl- 1-(2-fluoro-4-trifluoromethyl-501.2 phenyl)-[4-(2-fluoro-4-trifluoromethyl- phenyl)-piperazine andphenyl)-piperazin-1-yl]-methanone Compound 1.4 21(2-cyclopropylmethoxy-5-methanesulfonyl- 1-(3-fluoro-4-trifluoromethyl-501.2 phenyl)-[4-(3-fluoro-4- phenyl)-piperazine andtrifluoromethyl-phenyl)-piperazin- Compound 1.4 1-yl]-methanone 22(2-cyclopropylmethoxy-5-methanesulfonyl- 1-(2-fluoro-4-methanesulfonyl-511.3 phenyl)-[4-(2-fluoro-4- phenyl)-piperazine andmethanesulfonyl-phenyl)-piperazin- Compound 1.4 1-yl]-methanone 231-(3-fluoro-4-{4-[5-methanesulfonyl- 1-(3-fluoro-4-piperazin-1-yl- 503.12-(2,2,2-trifluoro-ethoxy)- phenyl)-ethanone and Compound 1.5benzoyl]-piperazin-1-yl}-phenyl)- ethanone 244-{4-[5-methanesulfonyl-2-(2,2,2- 4-piperazin-1-yl-benzonitrile and468.1 trifluoro-ethoxy)-benzoyl]- Compound 1.5piperazin-1-yl}-benzonitrile 25 3-fluoro-4-{4-[5-methanesulfonyl-2-3-fluoro-4-piperazin-1-yl-benzonitrile 468.2(2,2,2-trifluoro-ethoxy)-benzoyl]- and Compound 1.5piperazin-1-yl}-benzonitrile 26 2-fluoro-4-{4-[5-methanesulfonyl-2-2-fluoro-4-piperazin-1-yl-benzonitrile 486.2(2,2,2-trifluoro-ethoxy)-benzoyl]- and Compound 1.5piperazin-1-yl}-benzonitrile 27 [5-methanesulfonyl-2-(2,2,2-trifluoro-1-(4-trifluoromethyl-phenyl)- 511.2ethoxy)-phenyl]-[4-(4-trifluoromethyl- piperazine and Compound 1.5phenyl)-piperazin-1-yl]-methanone 28 [4-(2-fluoro-4-trifluoromethyl-1-(2-fluoro-4-trifluoromethyl- 529.2 phenyl)-piperazin-1-yl]-[5-phenyl)-piperazine and methanesulfonyl-2-(2,2,2-trifluoro- Compound 1.5ethoxy)-phenyl]-methanone 29 [4-(3-fluoro-4-trifluoromethyl-1-(3-fluoro-4-trifluoromethyl- 529.2phenyl)-piperazin-1-yl]-[5-methanesulfonyl- phenyl)-piperazine and2-(2,2,2-trifluoro- Compound 1.5 ethoxy)-phenyl]-methanone 30[4-(2-fluoro-4-methanesulfonyl- 1-(2-fluoro-4-methanesulfonyl- 539.2phenyl)-piperazin-1-yl]-[5-methanesulfonyl- phenyl)-piperazine and2-(2,2,2-trifluoro- Compound 1.5 ethoxy)-phenyl]-methanone 311-{4-[4-(2-cyclopentyloxy-5-methanesulfonyl-1-(3-fluoro-4-piperazin-1-yl- 489.2 benzoyl)-piperazin-1-phenyl)-ethanone and Compound 1.6 yl]-3-fluoro-phenyl}-ethanone 324-[4-(2-cyclopentyloxy-5-methanesulfonyl- 4-piperazin-1-yl-benzonitrileand 454.2 benzoyl)-piperazin-1-yl]- Compound 1.6 benzonitrile 334-[4-(2-cyclopentyloxy-5-methanesulfonyl- 3-fluoro-4-piperazin-1-yl-472.2 benzoyl)-piperazin-1-yl]-3- benzonitrile and Compound 1.6fluoro-benzonitrile 34 4-[4-(2-cyclopentyloxy-5-methanesulfonyl-2-fluoro-4-piperazin-1-yl- 472.2 benzoyl)-piperazin-1-yl]-2-benzonitrile and Compound 1.6 fluoro-benzonitrile 35(2-cyclopentyloxy-5-methanesulfonyl- 1-(2-fluoro-4-trifluoromethyl-515.2 phenyl)-[4-(2-fluoro-4-trifluoromethyl- phenyl)-piperazine andphenyl)-piperazin-1-yl]-methanone Compound 1.6 36(2-cyclopentyloxy-5-methanesulfonyl- 1-(3-fluoro-4-trifluoromethyl-515.2 phenyl)-[4-(3-fluoro-4- phenyl)-piperazine andtrifluoromethyl-phenyl)-piperazin- Compound 1.6 1-yl]-methanone 37(2-cyclopentyloxy-5-methanesulfonyl- 1-(2-fluoro-4-methanesulfonyl-525.3 phenyl)-[4-(2-fluoro-4- phenyl)-piperazine andmethanesulfonyl-phenyl)-piperazin- Compound 1.6 1-yl]-methanone 381-(3-fluoro-4-{4-[2-(4-fluoro-phenoxy)- 1-(3-fluoro-4-piperazin-1-yl-515.2 5-methanesulfonyl-benzoyl]- phenyl)-ethanone and Compound 1.7piperazin-1-yl}-phenyl)-ethanone 39 4-{4-[2-(4-fluoro-phenoxy)-5-4-piperazin-1-yl-benzonitrile and 480.2 methanesulfonyl-benzoyl]-Compound 1.7 piperazin-1-yl}-benzonitrile 403-fluoro-4-{4-[2-(4-fluoro-phenoxy)-3-fluoro-4-piperazin-1-yl-benzonitrile 498.2 5-methanesulfonyl-benzoyl]-and Compound 1.7 piperazin-1-yl}-benzonitrile 412-fluoro-4-{4-[2-(4-fluoro-phenoxy)-2-fluoro-4-piperazin-1-yl-benzonitrile 498.2 5-methanesulfonyl-benzoyl]-and Compound 1.7 piperazin-1-yl}-benzonitrile 42[2-(4-fluoro-phenoxy)-5-methanesulfonyl- 1-(4-trifluoromethyl-phenyl)-523.3 phenyl]-[4-(4-trifluoromethyl- piperazine and Compound 1.7phenyl)-piperazin-1-yl]-methanone 43[2-(4-fluoro-phenoxy)-5-methanesulfonyl- 1-(2-fluoro-4-trifluoromethyl-541.2 phenyl]-[4-(2-fluoro-4-trifluoromethyl- phenyl)-piperazine andphenyl)-piperazin-1-yl]-methanone Compound 1.7 44[2-(4-fluoro-phenoxy)-5-methanesulfonyl- 1-(3-fluoro-4-trifluoromethyl-541.2 phenyl]-[4-(3-fluoro-4- phenyl)-piperazine andtrifluoromethyl-phenyl)-piperazin- Compound 1.7 1-yl]-methanone 45[4-(2-fluoro-4-methanesulfonyl- 1-(2-fluoro-4-methanesulfonyl- 551.3phenyl)-piperazin-1-yl]-[2-(4- phenyl)-piperazine andfluoro-phenoxy)-5-methanesulfonyl- Compound 1.7 phenyl]-methanone 46[4-(2-fluoro-4-methanesulfonyl- 1-(2-fluoro-4-methanesulfonyl- 499.2phenyl)-piperazin-1-yl]-(2- phenyl)-piperazine andisopropoxy-5-methanesulfonyl- Compound 1.2 phenyl)-methanone 523-[4-(4-acetyl-2-fluoro-phenyl)- 1-(3-Fluoro-4-piperazin-1-yl- 434.2piperazine-1-carbonyl]-4-methoxy- phenyl)-ethanone and 2-benzenesulfonamide methoxy-5-sulfamoyl-benzoic acid 533-[4-(4-acetyl-2-fluoro-phenyl)- 1-(3-Fluoro-4-piperazin-1-yl- 448.2piperazine-1-carbonyl]-4-ethoxy- phenyl)-ethanone and 2-Ethoxy-5-benzenesulfonamide sulfamoyl-benzoic acid 541-(3-Fluoro-4-{4-[2-(2-methoxyethoxy)- 1-(3-Fluoro-4-piperazin-1-yl-446.1 5-nitro-benzoyl]-piperazin- phenyl)-ethanone and 2-(2-1-yl}-phenyl)-ethanone Methoxyethoxy)-5-nitrobenzoic acid

EXAMPLE 47 Preparation of1-{3-fluoro-4-[4-(2-methoxy-5-nitro-benzoyl)-piperazin-1-yl]-phenyl}-ethanone

To a solution of 0.257 mmol1-{3-fluoro-4-[4-(2-fluoro-5-nitro-benzoyl)-piperazin-1-yl]-phenyl}-ethanone(Compound 1.8) in 1.5 ml dioxane 102 mg sodium methoxyde was addedportionwise. The mixture was stirred at 100° C. for 4 h. The reactionmixture was diluted with 10 ml water, neutralized with 1N HCl and thenextracted with ethylacetate (3×10 ml). Combined organic phases wereconcentrated in vacuo. The residue was chromatographed on silicagel:eluent:heptane/ethylacetate 0%-30% (10 min) to provide compound 47.

MS (m/e): 402.2 (M+H⁺, 100%).

EXAMPLE 48 Preparation of(2-benzyloxy-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone

A mixture of 0.19 mmol(2-iodo-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone(Compound 1.9), 0.037 mmol CuI, 0.37 mmol Cs₂CO₃, 0.074 mmol1,10-phenanthroline and 0.4 ml benzylic alcohol was heated at 110° C.for 16 hours. The mixture was cooled to RT, diluted with ethylacetateand filtered. The organic layer was washed twice with water, dried overNa₂SO₄, filtered and the solvent was removed in vacuo. The crude oil waspurified on silica gel, eluent: heptane/ethylacetate 0%-50% (25 min) toprovide compound 48.

MS (m/e): 519.2 (M+H⁺, 100%)

In analogy to Example 48 compounds 49 to 51 of the following table wereprepared from(2-iodo-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone(Compound 1.9) and alcohols:

Expl. MW found No Systematic Name Starting materials (MH⁺) 49(2-ethoxy-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl- Compound 1.9and 457.2 phenyl)-piperazin-1-yl]-methanone ethanol 50(2-isopropoxy-5-methanesulfonyl-phenyl)-[4-(4- Compound 1.9 and 471.2trifluoromethyl-phenyl)-piperazin-1-yl]- isopropylalcohol methanone 51(2-cyclopentyloxy-5-methanesulfonyl-phenyl)- Compound 1.9 and 497.2[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]- cyclopentanol methanone

EXAMPLE 1.10 Preparation of5-Methanesulfonyl-2-(2-methoxy-ethoxy)-benzoic acid

(a) 2-Amino-5-methanesulfonyl-benzoic acid

A mixture of 4.26 mmol 2-chloro-5-methanesulfonyl-benzoic acid (compound1.2a), 0.39 mmol Copper powder and 10 ml ammonium hydroxide 25% washeated at 125-130° C. with stirring for 18 hours. The mixture was cooledto room temperature and filtered. The solid was washed with methanol.The filtrate was concentrated in vacuo. The residue was acidified withHCl 1N to pH=2. The obtained solid was washed with water and dried (HV,50° C., 1 hour) to yield the title compound. MS (m/e): 214.1 (M−H, 100%)

(b) 2-Iodo-5-methanesulfonyl-benzoic acid

To a suspension of 3.0 mmol 2-amino-5-methanesulfonyl-benzoic acid in amixture of 1.7 ml sulfuric acid and 1.7 ml water was added dropwise asolution of 3.92 mmol sodium nitrite in 1.7 ml water at such rate thatthe temperature did not exceed 3° C. The mixture was stirred at 0° C.for 1 hour. A solution of 3.0 mmol KI in 1.7 ml water was added dropwiseat 0° C. The brown suspension was allowed to warm to rt and stirred for30 minutes. Excess iodine was destroyed by addition of a few drops of asodium hydrogenosulfite solution. The solid was filtered, washed withwater and dried (HV, 50° C., 1 hour) to yield the title compound. MS(m/e): 325.0 (M−H, 100%)

(c) 5-Methanesulfonyl-2-(2-methoxy-ethoxy)-benzoic acid

To a solution of 1.6 mmol 2-iodo-5-methanesulfonyl-benzoic acid in 30 ml2-methoxyethanol and 6 ml triethylamine were added 79 mg copper(I)bomide, and the reaction mixture heated to 120° C. for 4 h. Thesolvent was distilled off, and the residue dissolved in 90 ml 1N HCl.The aqueous phase was extracted twice with ethyl acetate, and the pooledorganic extracts washed twice with water and once with brine. Theorganic layer was dried with Na₂SO₄, filtered and evaporated to yieldthe title compound 1.10. MS (m/e): 273.1 (MH⁻, 100%).

EXAMPLE 1.11 Preparation of 5-Cyano-2-(2-methoxy-ethoxy)-benzoic acid

(a) 2-Bromo-5-cyano-benzoic acid

To a suspension of 7.1 mmol copper (II) bromide in acetonitrile (30 ml)was added dropwise 8.63 mmol tert-butylnitrite at 0° C. within 2minutes. 6.17 mmol 2-Amino-5-cyano-benzoic acid (CAS: 99767-45-0;WO9518097) was added portionwise within 10 minutes at 0° C. The mixturewas stirred at 0° C. for 2 hours and then at room temperature overnight.Half of the solvent was removed in vacuo. The residue was taken in HCl1N (15 ml) and ethyl acetate (30 ml). The organic layer was extractedwith NaOH 1N (3×10 ml). The aqueous layer was acidified with HCl 2N. Theresulting solid was filtered, washed with water and dried (high vacuum,50° C.) to provide the title compound MS (m/e): 227.1 (M+H⁺, 100%)

(b) 5-Cyano-2-(2-methoxy-ethoxy)-benzoic acid

To a solution of 0.16 mmol 2-bromo-5-cyano-benzoic acid in 6 ml2-methoxyethanol and 1.2 ml triethylamine were added 23 mg copper (I)bromide, and the reaction mixture heated to 120° C. for 4 h. The solventwas distilled off, and the residue dissolved in 20 ml 1N HCl. Theaqueous phase was extracted twice with ethyl acetate, and the pooledorganic extracts washed twice with water and once with brine. Theorganic layer was dried with Na₂SO₄, filtered and evaporated to yieldthe title compound 1.11. MS (m/e): 220.4 (MH⁻, 100%).

EXAMPLE 1.12 Preparation of 5-Cyano-2-(2,2,2-trifluoro-ethoxy)-benzoicacid

A mixture of 11.3 mmol sodium in 66 mmol 2,2,2-trifluoroethanol washeated to 100° C. until all sodium was dissolved (20 min.). Then asolution of 5.5 mmol 5-cyano-2-iodo-benzoic acid [CAS: 219841-92-6;WO9901455] in 2 ml N-methyl-2-pyrrolidone and 0.5 mmol copper (I)bromide were added, and the reaction mixture heated to 120° C. for 2 h.The reaction mixture was poured onto water, acidified to pH 2 with conc.HCl and extracted 3× with ethyl acetate. The pooled organic extractswere washed with brine, dried over Na₂SO₄ and evaporated. Flashchromatography on silica gel with heptane/ethyl acetate provided thetitle compound 1.12. MS (EI) (m/e): 245.1 (M^(+.), 94%), 146.0([M−CF₃CH₂O]^(+.), 100%).

In analogy to Example 1.12 compounds 1.13 to 1.16 of the following tablewere prepared from 5-cyano-2-iodo-benzoic acid and the appropriatealcohol:

Compound Name Alcohol MS (m/e) 1.13 5-Cyano-2-isopropoxy-benzoic acidisopropanol 204.1 (M − H⁻, 100%) 1.14 5-Cyano-2-cyclopropylmethoxy-cyclopropyl-methanol 216.1 (M − H⁻, 100%) benzoic acid 1.155-Cyano-2-isobutoxy-benzoic acid isobutyl alcohol 218.3 (M − H⁻, 100%)1.16 5-Cyano-2-cyclopentyloxy-benzoic acid cyclopentanol 230.1 (M − H⁻,100%)

In analogy to Example 5 compounds 55 to 61 of the following table wereprepared from the acid derivatives and piperazine derivatives:

Expl. MW found No. Systematic Name Starting materials (MH⁺) 551-(3-Fluoro-4-{4-[5- 1-(3-Fluoro-4-piperazin-1- 479.5methanesulfonyl-2-(2-methoxyethoxy)- yl-phenyl)-ethanonebenzoyl]-piperazin-1-yl}- (WO9714690) and 5- phenyl)-ethanoneMethanesulfonyl-2-(2- methoxy-ethoxy)-benzoic acid (compound 1.10) 564-(2-Methoxy-ethoxy)-3-[4-(4- 1-(4-Trifluoromethyl- 434.5trifluoromethyl-phenyl)- phenyl)-piperazine and 5-piperazine-1-carbonyl]- cyano-2-(2-methoxy- benzonitrile ethoxy)-benzoicacid (compound 1.11) 57 4-(2,2,2-Trifluoro-ethoxy)-3-[4-1-(4-trifluoromethylphenyl) 458.4 (4-trifluoromethyl-phenyl)- piperazineand 5-Cyano-2- piperazine-1-carbonyl]- (2,2,2-trifluoro-ethoxy)-benzonitrile benzoic acid (compound 1.12) 58 4-Isopropoxy-3-[4-(4-1-(4-trifluoromethylphenyl) 418.3 trifluoromethyl-phenyl)- piperazineand 5-Cyano-2- piperazine-1-carbonyl]- isopropoxy-benzoic acidbenzonitrile (compound 1.13) 59 4-Cyclopropylmethoxy-3-[4-(4-1-(4-trifluoromethylphenyl) 430.6 trifluoromethyl-phenyl)- piperazineand 5-Cyano-2- piperazine-1-carbonyl]- cyclopropylmethoxy- benzonitrilebenzoic acid (compound 1.14) 60 4-Isobutoxy-3-[4-(4-1-(4-trifluoromethylphenyl) 432.5 trifluoromethyl-phenyl)- piperazineand 5-Cyano-2- piperazine-1-carbonyl]- isobutoxy-benzoic acidbenzonitrile (compound 1.15) 61 4-Cyclopentyloxy-3-[4-(4-1-(4-trifluoromethylphenyl) 444.5 trifluoromethyl-phenyl)- piperazineand 5-Cyano-2- piperazine-1-carbonyl]- cyclopentyloxy-benzoic acidbenzonitrile (compound 1.16)

EXAMPLE 2.1 Preparation of(2-Hydroxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin1-yl]-methanone

Compound 2.1 was prepared in analogy to Example 5 using2-hydroxy-5-nitrobenzoic acid [96-97-9] and1-(4-trifluoromethyl-phenyl)-piperazine. MS (m/e): 394.0 (M−H, 100%)

EXAMPLE 2.2 Preparation of(2-Hydroxy-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone

Compound 2.2 was prepared in analogy to Example 5 using2-hydroxy-5-(methylsulfonyl)benzoic acid [68029-77-6] and1-(4-trifluoromethyl-phenyl)-piperazine. MS (m/e): 427.5 (M−H, 100%)

EXAMPLE 66 Preparation of(2-Butoxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone

A solution of(2-Hydroxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone(50 mg), potassium carbonate (87 mg) and 1-bromobutane (0.15 mL) indimethylacetamide (0.3 mL) was heated at 150° C. for 15 minutes in amicrowave oven. The reaction mixture was then concentrated and purifiedby column chromatography (SiO₂) to give the title compound (55 mg).

In analogy to Example 66, compounds 62 to 97 of the following table wereprepared from the acid derivatives and piperazine derivatives:

Expl. MW found No. Systematic Name Starting materials (MH⁺) 62(2-Isopropoxy-5-nitro- (2-Hydroxy-5-nitro-phenyl)-[4- 438.4phenyl)-[4-(4- (4-trifluoromethyl-phenyl)- trifluoromethyl-phenyl)-piperazin-1-yl]-methanone piperazin-1-yl]-methanone (compound 2.1) and2- bromopropane 63 (2-Cyclopropylmethoxy-5-(2-Hydroxy-5-nitro-phenyl)-[4- 450.5 nitro-phenyl)-[4-(4-(4-trifluoromethyl-phenyl)- trifluoromethyl-phenyl)-piperazin-1-yl]-methanone piperazin-1-yl]-methanone (compound 2.1) andcyclopropylmethylbromide 64 (2-Cyclobutylmethoxy-5-(2-Hydroxy-5-nitro-phenyl)-[4- 464.5 nitro-phenyl)-[4-(4-(4-trifluoromethyl-phenyl)- trifluoromethyl-phenyl)-piperazin-1-yl]-methanone piperazin-1-yl]-methanone (compound 2.1) andCyclobutylmethylbromide 65 (2-Allyloxy-5- (2-Hydroxy-5-methanesulfonyl-469.5 methanesulfonyl-phenyl)- phenyl)-[4-(4-trifluoromethyl-[4-(4-trifluoromethyl- phenyl)-piperazin-1-yl]- phenyl)-piperazin-1-yl]-methanone (compound 2.2) methanone and cyclopropylbromide 66(2-Butoxy-5-nitro-phenyl)- (2-Hydroxy-5-nitro-phenyl)-[4- 452.4[4-(4-trifluoromethyl- (4-trifluoromethyl-phenyl)-phenyl)-piperazin-1-yl]- piperazin-1-yl]-methanone methanone (compound2.1) and bromobutane 67 Rac-[2-(2-Hydroxy-(2-Hydroxy-5-nitro-phenyl)-[4- 454.6 propoxy)-5-nitro-phenyl]-(4-trifluoromethyl-phenyl)- [4-(4-trifluoromethyl-piperazin-1-yl]-methanone phenyl)-piperazin-1-yl]- (compound 2.1) andrac-1- methanone Bromo-2-propanol 68 [2-(2,2-Dimethyl-propoxy)-(2-Hydroxy-5-nitro-phenyl)-[4- 466.6 5-nitro-phenyl]-[4-(4-(4-trifluoromethyl-phenyl)- trifluoromethyl-phenyl)-piperazin-1-yl]-methanone piperazin-1-yl]-methanone (compound 2.1) and1-Bromo- 2,2-Dimethylpropane 69 [2-(3-Methyl-butoxy)-5-(2-Hydroxy-5-nitro-phenyl)-[4- 466.5 nitro-phenyl]-[4-(4-(4-trifluoromethyl-phenyl)- trifluoromethyl-phenyl)-piperazin-1-yl]-methanone piperazin-1-yl]-methanone (compound 2.1) and1-Bromo- 3-methylbutane 70 (2-Isobutoxy-5-nitro-(2-Hydroxy-5-nitro-phenyl)-[4- 452.5 phenyl)-[4-(4-(4-trifluoromethyl-phenyl)- trifluoromethyl-phenyl)-piperazin-1-yl]-methanone piperazin-1-yl]-methanone (compound 2.1) and1-Bromo- 3-methylpropane 71 (2-Cyclopentyloxy-5-nitro-(2-Hydroxy-5-nitro-phenyl)-[4- 464.5 phenyl)-[4-(4-(4-trifluoromethyl-phenyl)- trifluoromethyl-phenyl)-piperazin-1-yl]-methanone piperazin-1-yl]-methanone (compound 2.1) andCyclopentyl bromide 72 (5-Nitro-2-propoxy-(2-Hydroxy-5-nitro-phenyl)-[4- 438.5 phenyl)-[4-(4-(4-trifluoromethyl-phenyl)- trifluoromethyl-phenyl)-piperazin-1-yl]-methanone piperazin-1-yl]-methanone (compound 2.1) and1- Bromopropane 73 (2-Cycloheptyloxy-5-nitro-(2-Hydroxy-5-nitro-phenyl)-[4- 492.5 phenyl)-[4-(4-(4-trifluoromethyl-phenyl)- trifluoromethyl-phenyl)-piperazin-1-yl]-methanone piperazin-1-yl]-methanone (compound 2.1) andBromocycloheptane 74 (2-Cyclobutoxy-5-nitro-(2-Hydroxy-5-nitro-phenyl)-[4- 450.4 phenyl)-[4-(4-(4-trifluoromethyl-phenyl)- trifluoromethyl-phenyl)-piperazin-1-yl]-methanone piperazin-1-yl]-methanone (compound 2.1) andBromocyclobutane 75 [2-(2-Ethoxy-ethoxy)-5-(2-Hydroxy-5-nitro-phenyl)-[4- 468.5 nitro-phenyl]-[4-(4-(4-trifluoromethyl-phenyl)- trifluoromethyl-phenyl)-piperazin-1-yl]-methanone piperazin-1-yl]-methanone (compound 2.1) and2- Bromoethyl-ethylether 76 [2-((R)-3-Hydroxy-2-(2-Hydroxy-5-nitro-phenyl)-[4- 468.4 methyl-propoxy)-5-nitro-(4-trifluoromethyl-phenyl)- phenyl]-[4-(4- piperazin-1-yl]-methanonetrifluoromethyl-phenyl)- (compound 2.1) and (R)-(−)-3-piperazin-1-yl]-methanone bromo-2-methyl-1-propanol 77(2-Ethoxy-5-nitro-phenyl)- (2-Hydroxy-5-nitro-phenyl)-[4- 424.4[4-(4-trifluoromethyl- (4-trifluoromethyl-phenyl)-phenyl)-piperazin-1-yl]- piperazin-1-yl]-methanone methanone (compound2.1) and 2-Bromo- 1-ethoxy-1,1,2-trifluoro-ethane 78Rac-(2-sec-Butoxy-5-nitro- Rac-(2-Hydroxy-5-nitro- 452.5 phenyl)-[4-(4-phenyl)-[4-(4-trifluoromethyl- trifluoromethyl-phenyl)-phenyl)-piperazin-1-yl]- piperazin-1-yl]-methanone methanone (compound2.1) and 2-Bromobutane 79 [2-(2-Hydroxy-ethoxy)-5-(2-Hydroxy-5-nitro-phenyl)-[4- 440.4 nitro-phenyl]-[4-(4-(4-trifluoromethyl-phenyl)- trifluoromethyl-phenyl)-piperazin-1-yl]-methanone piperazin-1-yl]-methanone (compound 2.1) and2-Bromo- 1-ethanol 80 [5-Nitro-2-(2,2,3,3-(2-Hydroxy-5-nitro-phenyl)-[4- 510.5 tetrafluoro-propoxy)-(4-trifluoromethyl-phenyl)- phenyl]-[4-(4- piperazin-1-yl]-methanonetrifluoromethyl-phenyl)- (compound 2.1) and 1-Iodo-piperazin-1-yl]-methanone 2,2,3,3,-tetrafluoropropane 81[5-Nitro-2-(4,4,4-trifluoro- (2-Hydroxy-5-nitro-phenyl)-[4- 506.5butoxy)-phenyl]-[4-(4- (4-trifluoromethyl-phenyl)-trifluoromethyl-phenyl)- piperazin-1-yl]-methanonepiperazin-1-yl]-methanone (compound 2.1) and 1-Bromo-4,4,4,-trifluorobutane 82 [2-(2-Fluoro-ethoxy)-5-(2-Hydroxy-5-nitro-phenyl)-[4- 442.5 nitro-phenyl]-(4-trifluoromethyl-phenyl)- [4-(4-trifluoromethyl-piperazin-1-yl]-methanone phenyl)-piperazin- (compound 2.1) and 1-Bromo-1-yl]-methanone 2-fluoroethane 83 [2-(3-Hydroxy-2,2-(2-Hydroxy-5-nitro-phenyl)-[4- 482.6 dimethyl-propoxy)-(4-trifluoromethyl-phenyl)- 5-nitro-phenyl]-[4-(4-piperazin-1-yl]-methanone trifluoromethyl-phenyl)- (compound 2.1) and3-Bromo- piperazin-1-yl]-methanone 2,2-Dimethyl-2-propan-1-ol 84[5-Nitro-2-(2,2,2-trifluoro- (2-Hydroxy-5-nitro-phenyl)-[4- 478.3ethoxy)-phenyl]-[4-(4- (4-trifluoromethyl-phenyl)-trifluoromethyl-phenyl)- piperazin-1-yl]-methanonepiperazin-1-yl]-methanone (compound 2.1) and 1,1,1-Trifluoro-2-iodo-ethane 85 [2-(1-Ethyl-propoxy)-5-(2-Hydroxy-5-nitro-phenyl)-[4- 466.5 nitro-phenyl]-(4-trifluoromethyl-phenyl)- [4-(4-trifluoromethyl-piperazin-1-yl]-methanone phenyl)-piperazin- (compound 2.1) and 3-Bromo-1-yl]-methanone pentane 86 [5-Nitro-2-(oxetan-3-(2-Hydroxy-5-nitro-phenyl)-[4- 452.4 yloxy)-phenyl]-[4-(4-(4-trifluoromethyl-phenyl)- trifluoromethyl-phenyl)-piperazin-1-yl]-methanone piperazin-1-yl]-methanone (compound 2.1) andToluene-4- sulfonic acid oxetan-3-yl ester (CAS: 26272-83-3) 87[2-(3-Hydroxy-propoxy)-5- (2-Hydroxy-5-nitro-phenyl)-[4- 454.6nitro-phenyl]-[4-(4- (4-trifluoromethyl-phenyl)-trifluoromethyl-phenyl)- piperazin-1-yl]-methanonepiperazin-1-yl]-methanone (compound 2.1) and Bromopropanole 88[2-(Bicyclo[2.2.1]hept-2- (2-Hydroxy-5-nitro-phenyl)-[4- 490.5yloxy)-5-nitro-phenyl]- (4-trifluoromethyl-phenyl)-[4-(4-trifluoromethyl- piperazin-1-yl]-methanonephenyl)-piperazin-1-yl]- (compound 2.1) and exo-2- methanoneBromonorbornane 89 [2-(2-Methoxy-ethoxy)-5-(2-Hydroxy-5-nitro-phenyl)-[4- 454.5 nitro-phenyl]-(4-trifluoromethyl-phenyl)- [4-(4-trifluoromethyl-piperazin-1-yl]-methanone phenyl)-piperazin-1-yl]- (compound 2.1) and 2-methanone bromoethylmethylether 90 [2-(3,3-Dimethyl-butoxy)-(2-Hydroxy-5-nitro-phenyl)-[4- 480.8 5-nitro-phenyl]-[4-(4-(4-trifluoromethyl-phenyl)- trifluoromethyl-phenyl)-piperazin-1-yl]-methanone piperazin-1-yl]-methanone (compound 2.1) and1-bromo- 3,3-dimethylbutane 91 [2-(1-Ethoxy-(2-Hydroxy-5-nitro-phenyl)-[4- 480.6 cyclopropoxy)-5-nitro-(4-trifluoromethyl-phenyl)- phenyl]-[4-(4- piperazin-1-yl]-methanonetrifluoromethyl-phenyl)- (compound 2.1) and 1-Bromo- piperazin-1-yl]-1-ethoxy-cyclopropane methanone 92 [2-(2-Chloro-ethoxy)-5-(2-Hydroxy-5-nitro-phenyl)-[4- 458.4 nitro-phenyl]-(4-trifluoromethyl-phenyl)- [4-(4-trifluoromethyl-piperazin-1-yl]-methanone phenyl)-piperazin- (compound 2.1) and 2-1-yl]-methanone Chloroethanol 93 {4-Nitro-2-[4-(4-(2-Hydroxy-5-nitro-phenyl)-[4- 435.4 trifluoromethyl-phenyl)-(4-trifluoromethyl-phenyl)- piperazine-1-carbonyl]-piperazin-1-yl]-methanone phenoxy}-acetonitrile (compound 2.1) andbromoacetonitrile 94 [5-Nitro-2-(3,3,3-trifluoro-(2-Hydroxy-5-nitro-phenyl)-[4- 492.4 propoxy)-phenyl]-[4-(4-(4-trifluoromethyl-phenyl)- trifluoromethyl-phenyl)-piperazin-1-yl]-methanone piperazin-1-yl]-methanone (compound 2.1) and1,1,1- Trifluoro-1-Iodopropan 95 [5-Nitro-2-(tetrahydro-(2-Hydroxy-5-nitro-phenyl)-[4- 480.4 pyran-4-yloxy)-phenyl]-[4-(4-trifluoromethyl-phenyl)- (4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone piperazin-1-yl]-methanone (compound 2.1) and4-chloro- tetrahydropyrane 96 [2-(2,2-Difluoro-ethoxy)-5-(2-Hydroxy-5-nitro-phenyl)-[4- 460.5 nitro-phenyl]-[4-(4-(4-trifluoromethyl-phenyl)- trifluoromethyl-phenyl)-piperazin-1-yl]-methanone piperazin-1-yl]-methanone (compound 2.1) and1-bromo- 2,2-difluoroethane 97 [2-(1,1,2,3,3,3-Hexafluoro-(2-Hydroxy-5-nitro-phenyl)-[4- 546.3 propoxy)-5-nitro-phenyl]-(4-trifluoromethyl-phenyl)- [4-(4-trifluoromethyl-piperazin-1-yl]-methanone phenyl)-piperazin-1-yl]- (compound 2.1) and 3-methanone Hexafluoropropane

EXAMPLE 98 Preparation of(2-Difluoromethoxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone

In analogy to a procedure published in WO9749710, a solution of(2-Hydroxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone(50 mg), potassium carbonate (1 eq), and ethyl chlorofluoroacetate (1eq) in DMF (1 mL) was stirred at 65° C. for 16 hours. After such timethe reaction mixture was concentrated in vacuo and purified by columnchromatography (SiO₂) to yield the title compound (26 mg). MS (m/e):446.0 (M+H⁺, 100%).

EXAMPLE 99 Preparation of5-Nitro-2-(2,2,3,3-tetrafluoro-cyclobutylmethoxy)-phenyl-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone

Example 99 was prepared in analogy to Example 66 using1-(chloromethyl)-2,2,3,3-tetrafluorocyclobutane [356-80-9]. MS (m/e):536.3 (M+H⁺, 100%).

EXAMPLE 100 Preparation of[5-Nitro-2-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone

To a refluxing solution of 50 mg of(2-hydroxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanonein acetone (2 mL) containing potassium carbonate (35 mg) was added2,2,3,3,3-pentafluoropropyl trifluoromethanesulfonate (54 mg) over 10min. The reaction mixture was refluxed for 20 hours before beingconcentrated in vacuo and purified by column chromatography (SiO₂,CH₂Cl₂/MeOH) to yield the title compound as a colorless solid (66 mg).MS (m/e): 569.0 (M+H⁺, 100%).

EXAMPLE 101 Preparation of[2-(2-Fluoro-1-fluoromethyl-ethoxy)-5-nitro-phenyl]-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone

A solution of(2-hydroxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone(50 mg), 1,3-difluoro-2-propanol [453-13-4] (27 mg), triphenylphosphine(76 mg) and diisopropylazodicarboxylate (48 mg) was refluxed overnight,concentrated in vacuo and purified by column chromatography (SiO₂) toyield the title compound as a colorless solid (68 mg). MS (m/e): 474.1(M+H⁺, 100%).

In analogy to Example 48, compounds 102 to 104 of the following tablewere prepared from(2-Iodo-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone(compound 1.9) and an alcohol:

MW Expl. found No. Systematic Name Starting materials (MH⁺) 102[2-(1-Ethyl-propoxy)-5- (2-Iodo-5-methanesulfonyl- 499.5methanesulfonyl-phenyl]- phenyl)-[4-(4-trifluoromethyl-[4-(4-trifluoromethyl- phenyl)-piperazin-1-yl]- phenyl)-piperazin-1-yl]-methanone (compound 1.9) and methanone 3-Pentanol 103[5-Methanesulfonyl-2-(3- (2-Iodo-5-methanesulfonyl- 513.4methyl-oxetan-3- phenyl)-[4-(4-trifluoromethyl-ylmethoxy)-phenyl]-[4-(4- phenyl)-piperazin-1-yl]-trifluoromethyl-phenyl)- methanone (compound 1.9) andpiperazin-1-yl]-methanone Methyloxethanemethanol 104Rac-[2-(1-Cyclopropyl- (2-Iodo-5-methanesulfonyl- 497.4ethoxy)-5-methanesulfonyl- phenyl)-[4-(4-trifluoromethyl- phenyl]-[4-(4-phenyl)-piperazin-1-yl]- trifluoromethyl-phenyl)- methanone (compound1.9) and piperazin-1-yl]-methanone rac-1-cyclopropylethanol

EXAMPLE 2.3 Preparation of(2-Fluoro-5-methanesulfonyl-phenyl)-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone

Compound 2.3 was prepared in analogy to Example 5 using2-fluoro-5-(methylsulfonyl)benzoic acid [247569-56-8] and1-(5-trifluoromethyl-2-pyridyl)piperazine [132834-58-3]. MS (m/e): 432.4(M+H⁺, 100%).

EXAMPLE 105 Preparation of[5-Methanesulfonyl-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-phenyl]-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone

A solution of(2-fluoro-5-methanesulfonyl-phenyl)-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone(compound 2.3) (20 mg), 2-trifluoromethyl-2-propanol (0.053 mL),potassium carbonate or cesium carbonate (3 equivalents) indimethylacetamide was heated at 150° C. for 30 min and then at 180° C.for 1 h in a microwave oven. After such time the reaction mixture wasconcentrated and purified by column chromatography (SiO₂) to yield thetitle compound as a light yellow solid (4.9 mg). MS (m/e): 540.3 (M+H⁺,100%).

EXAMPLE 2.4 Preparation of(2-Isopropoxy-5-methanesulfonyl-phenyl)-piperazin-1-yl-methanonetrifluoro-acetic acid

A solution of 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1.2,1.0 g), tert-butyl 1-piperazinecarboxylate (0.78 g), TBTU (1.4 g) andN-ethyldiisopropylamine (4 mL) was stirred at room temperature for 2hours. After such time, the reaction mixture was concentrated in vacuoand purified by column chromatography (SiO₂) to give4-(2-Isopropoxy-5-methanesulfonyl-benzoyl)-piperazine-1-carboxylic acidtert-butyl ester as a colorless foam (1.6 g). The latter was dissolvedin dichloromethane (11 mL) and treated with trifluroacetic acid (4.2 mL)for 30 minutes. After such time the reaction mixture was concentrated invacuo to yield the title compound (1.6 g) as light yellow oil. MS (m/e):327.1 (M+H⁺, 100%).

EXAMPLE 2.5 Preparation of 4-Chloro-6-trifluoromethyl-pyrimidine

6-Trifluoromethyl-pyrimidin-4-ol ([1546-78-7], 5 g) was refluxed inphosphorus oxychloride (17 mL) for 2 hours. The reaction mixture wascarefully concentrated in vacuo and the residue was distilled(Kugelrohr) under reduced pressure (bp=30-55° C. @ 10 mbar) to yield thetitle compound ([37552-81-1], 1.4 g). MS (EI): 182.0 (M).

EXAMPLE 106 Preparation of(2-Isopropoxy-5-methanesulfonyl-phenyl)-[4-(5-nitro-pyridin-2-yl)-piperazin-1-yl]-methanone

A solution of(2-isopropoxy-5-methanesulfonyl-phenyl)-piperazin-1-yl-methanonetrifluoro-acetic acid (compound 2.4, 80 mg) 2-chloro-5-nitro-pyridine(29 mg), potassium carbonate (50 mg) in 1-butanol (3 mL) was stirred at120° C. for 20 hours. After such time the solution was concentrated invacuo, and purified by column chromatography (SiO2) to yield the titlecompound as white foam (81 mg). MS (m/e): 449.1 (M+H⁺, 100%).

EXAMPLE 107 Preparation of(2-Isopropoxy-5-methanesulfonyl-phenyl)-[4-(6-trifluoromethyl-pyrimidin-4-yl)-piperazin-1-yl]-methanone

Example 107 was prepared in analogy to example 106 using4-chloro-6-trifluoromethyl-pyrimidine [37552-81-1]. MS (m/e): 473.1(M+H⁺, 100%).

EXAMPLE 2.6 Preparation of 2-(4-fluorophenoxy)-5-nitrobenzoic acid

2-(4-Fluoro-phenoxy)-5-nitro-benzoic acid can be prepared by a similarmethod to that described in the literature (e.g. WO9938845) by reactionof 2-Chloro-5-nitro-benzoic acid ethyl ester [16588-17-3] with4-Fluoro-phenol [371-35-7] yielding 2-(4-Fluoro-phenoxy)-5-nitro-benzoicacid ethyl ester. 2-(4-Fluoro-phenoxy)-5-nitro-benzoic acid ethyl estercan then be hydrolysed with sodium hydroxide for example to yield thetitle compound. MS (m/e): 276.1 (M+H⁺, 100%).

EXAMPLE 2.7 Preparation of2,3-Difluoro-4-piperazin-1-yl-benzonitrile-trifluoro-acetic acid

(a) 4-(4-Cyano-2,3-difluoro-phenyl)-piperazine-1-carboxylic acidtert-butyl ester

To a solution of N-Boc-Piperazine (0.65 g) in DMA (20 mL) was slowlyadded a solution of 2,3,4-trifluorobenzonitrile (0.49 g) in DMA (10 mL).The reaction mixture was stirred for 2 hours at 80° C. After such timethe solvent was removed in vacuo and purified by column chromatography(SiO₂) to yield the title compound as white solid (0.76 g).

(b) 2,3-Difluoro-4-piperazin-1-yl-benzonitrile-trifluoro-acetic acid

To a solution of 4-(4-Cyano-2,3-difluoro-phenyl)-piperazine-1-carboxylicacid tert-butyl ester (0.72 g) in dichloromethane (5 mL) was addedtrifluoroacetic acid, and the reaction mixture was stirred at roomtemperature for 30 minutes. After such time the reaction mixture wasconcentrated in vacuo to yield the title compound (0.63 g). MS (m/e):224.3 (M+H⁺, 100%).

EXAMPLE 2.8 Preparation of2,5-Difluoro-4-piperazin-1-yl-benzonitrile-trifluoro-acetic acid

Example 2.8 was prepared in analogy to Example 2.7 using2,4,5-trifluorobenzonitrile. MS (m/e): 224.3 (M+H⁺, 100%).

EXAMPLE 2.9 Preparation of 5-Methylsulfamoyl-2-trifluoromethoxy-benzoicacid

(a) 5-Chlorosulfonyl-2-trifluoromethoxy-benzoic acid

A solution of 2-trifluoromethoxy benzoic acid [1979-29-9] (1.0 g) wasadded in small batches to chlorosulfonic acid (3.2 mL) at 0° C. Aftercompletion of the addition, the reaction mixture was stirred at 70° C.for 4 hours then left at room temperature overnight and heated at 75° C.for another 3 hours. After such time the reaction was slowly poured ontoice, and the precipitate was then filtered, washed with water and driedto yield the title compound as a white solid (1.2 g). MS (m/e): 303.3(M−H, 100%).

(b) 5-Methylsulfamoyl-2-trifluoromethoxy-benzoic acid

To a solution of 5-Chlorosulfonyl-2-trifluoromethoxy-benzoic acid (0.15g) in dichloromethane (1.5 ml) was added a solution of methylamine inmethanol (8M, 0.31 mL), and the reaction mixture was stirred for 2minutes after precipitation was complete. The reaction mixture was thenconcentrated in vacuo and the residue was dissolved in 1N NaOH (2 mL)and extracted with diethylether. The aqueous phase was then acidifiedusing 3 N hydrochloric acid solution (2 mL), and the solution wasextracted with dichloromethane (2×10 mL). The combined organic phaseswere dried with sodium sulfate and concentrated in vacuo to yield thetitle compound as a white solid (0.12 g). MS (m/e): 298.0 (M−H, 100%).

EXAMPLE 2.10 Preparation of5-Methanesulfonyl-2-(3,3,3-trifluoro-propoxy)-benzoic acid

(a) 5-Methanesulfonyl-2-(3,3,3-trifluoro-propoxy)-benzoic acid methylester

A solution of methyl 5-(methanesulfonyl)-salicylate [101371-44-2] (50mg), triphenylphosphine (65 mg) 3,3,3-trifluoro-1-propanol anddi-tert-butyl azodicarboxylate (55 mg) in THF (3 mL) was stirred at roomtemperature for 1 hour. The reaction mixture was then concentrated invacuo and purified by column chromatography (SiO₂) to yield the titlecompound as a white solid (65 mg). MS (m/e): 327.5 (M+H⁺, 100%).

(b) 5-Methanesulfonyl-2-(3,3,3-trifluoro-propoxy)-benzoic acid

To 5-methanesulfonyl-2-(3,3,3-trifluoro-propoxy)-benzoic acid methylester (620 mg) in ethanol at 60° C. was added 1N NaOH solution (3.8 mL),and the reaction mixture was stirred for 15 minutes. After such time,3.8 ml of 1N HCl was slowly added to the reaction mixture, and theethanol was evaporated in vacuo. The precipitate was then washed withwater several times to give the title compound (497 mg). MS (m/e):311.0, M−H⁺, 100%).

EXAMPLE 2.11 Preparation of5-Methanesulfonyl-2-(tetrahydro-pyran-4-yloxy)-benzoic acid

Compound 2.11 was prepared in analogy to compound 2.10 usingtetrahydro-2H-pyran-4-ol. MS (m/e): 299.4 (M−H, 100%).

EXAMPLE 2.12 Preparation of2-Cyclobutylmethoxy-5-methanesulfonyl-benzoic acid

Compound 2.12 was prepared in analogy to compound 2.10 using cyclobutylmethanol. MS (m/e): 299.4 (M−H, 100%).

EXAMPLE 2.13 Preparation of 3,5-Difluoro-4-piperazin-1-yl-benzonitriletrifluoro-acetic acid

Compound 2.13 was prepared in analogy to compound 2.7 using3,4,5-trifluorobenzonitrile. MS (m/e): 224.1 (M+H⁺, 100%).

EXAMPLE 2.14 Preparation of 2,6-Difluoro-4-piperazin-1-yl-benzonitriletrifluoro-acetic acid

Compound 2.14 was prepared in analogy to compound 2.7 using2,4,6-trifluorobenzonitrile. MS (m/e): 224.1 (M+H⁺, 100%).

EXAMPLE 2.15 Preparation of 5-Methanesulfonyl-2-trifluoromethoxy-benzoicacid

(a) 5-Sulfino-2-trifluoromethoxy-benzoic acid

5-chlorosulfonyl-2-trifluoromethoxy-benzoic acid (1.0 g, compound 2.9.a)was added portionwise onto a solution of sodium sulfite (3.1 g) in 16 mLof water. The reaction mixture was kept under basic conditions by theaddition of the proper amount of 20% NaOH and was stirred at roomtemperature for 45 minutes. After such time the reaction mixture wascooled down with an ice bath and was then acidified by the addition of20% H₂SO₄ solution until reaching pH 2. The solution was then extractedseveral times with diethyl ether and ethyl acetate. The combined organicphases were dried (sodium sulfate) and concentrated in vacuo to yieldthe title compound as a white solid (0.88 g).

(b) 5-Methanesulfonyl-2-trifluoromethoxy-benzoic acid

To 5-Sulfino-2-trifluoromethoxy-benzoic acid (0.82 g) in DMF (5 mL) wasadded 1.3 g of potassium carbonate, and the reaction mixture was stirredfor 5 minutes before methyl iodide (0.66 mL) was added. The reactionmixture was then stirred at room temperature for 60 hours. After suchtime the reaction mixture was concentrated in vacuo, and the residue wastreated with 1N NaOH (10 mL) and THF (4 mL). The reaction mixture wasstirred for a further 2 hours at room temperature. After such time thesolution was acidified with concentrated HCl solution. THF was thenremoved in vacuo) and the precipitate was isolated by filtration andwashed several times with water to yield the title compound. MS (m/e):283.0 (M−H, 100%).

EXAMPLE 2.16 Preparation of 2,4-Difluoro-6-piperazin-1-yl-benzonitriletrifluoro-acetic acid

Compound 2.16 was prepared in analogy to compound 2.7 using2,4,6-trifluorobenzonitrile of. MS (m/e): 224.1 (M+H⁺, 100%).

EXAMPLE 2.17 Preparation of2-(2-Fluoro-1-fluoromethyl-ethoxy)-5-methanesulfonyl-benzoic acid

Compound 2.17 was prepared in analogy to compound 2.10 using1,3-difluoro-2-propanol. MS (m/e): 293.1 (M−H, 100%).

EXAMPLE 2.18 Preparation of5-Methanesulfonyl-2-(2,2,3,3,3-pentafluoro-propoxy)-benzoic acid

(a) 5-Methanesulfonyl-2-(2,2,3,3,3-pentafluoro-propoxy)-benzoic acidmethyl ester

A solution of methyl 5-(methanesulfonyl)salicylate [101371-44-2] (0.50g), trifluoro-methanesulfonic acid 2,2,3,3,3-pentafluoro-propyl ester(0.67 g) and potassium carbonate (0.60 g) in acetone was stirred at 60°C. for 5 hours. The reaction mixture was then concentrated in vacuo andpurified by column chromatography (SiO₂) to yield the title compound asa white solid (0.44 g). MS (m/e): 363.1 (M+H⁺, 100%).

(b) 5-Methanesulfonyl-2-(2,2,3,3,3-pentafluoro-propoxy)-benzoic acid

To 5-methanesulfonyl-2-(2,2,3,3,3-pentafluoro-propoxy)-benzoic acidmethyl ester (414 mg) in THF (5 mL) was added a solution of lithiumhydroxide monohydrate (72 mg) in water (5 mL), and the reaction mixturewas stirred at room temperature for 1 hour. After such time 1.72 mL of1N aqueous hydrochloric acid solution was added. The reaction mixturewas then concentrated in vacuo, and the resulting precipitate was thenwashed several times with water to yield the title compound as a whitesolid (367 mg). MS (m/e): 347.1 (M−H, 100%).

EXAMPLE 2.19 Preparation of 2-tert-Butoxy-5-methanesulfonyl-benzoic acid

(a) 2-tert-Butoxy-5-methanesulfonyl-benzoic acid methyl ester

To a solution of methyl 5-(methanesulfonyl)-salicylate [101371-44-2](0.50 g) in toluene (5 mL) was addedN,N-dimethylformamide-di-tert-butylacetal, and the reaction mixture wasstirred at 80° C. for 1 hour. After such time the reaction mixture wasconcentrated in vacuo and purified by column chromatography to yield thetitle compound as colourless oil (258 mg). MS (m/e): 304.4 (M+NH₄ ⁺,100%).

(b) 2-tert-Butoxy-5-methanesulfonyl-benzoic acid

To 2-tert-Butoxy-5-methanesulfonyl-benzoic acid methyl ester (1.58 g) inTHF (25 mL) was added a solution lithium hydroxide monohydrate (0.35 g)in water (25 mL), and the reaction mixture was stirred at roomtemperature for 4 hours. After such time, the THF was removed in vacuoand to the remaining aqueous solution was added 8 mL of 1N HCl solution,leading to precipitation of the compound. The precipitate was filteredoff and washed several times with water to yield the title compound(1.00 g) as a white solid. MS (m/e): 289.9 (M+NH₄ ⁺).

EXAMPLE 2.20 Preparation of1-(2,5-Difluoro-4-methanesulfonyl-phenyl)-piperazine trifluoro-aceticacid

(a) 2,4,5-Trifluoro-benzenesulfinic acid

2,4,5-Trifluoro-benzenesulfonyl chloride ([220227-21-4], 2.5 g) wasadded portionwise onto a solution of sodium sulfite (10.3 g) in 50 mL ofwater. The reaction mixture was kept under basic conditions by theaddition of the proper amount of 20% NaOH and was stirred at roomtemperature for 1 hour. Methanol was added to the reaction mixture, andthe reaction mixture was stirred at room temperature for another hour.After such time, the reaction mixture was cooled down with an ice bathand was then acidified by the addition of 20% H₂SO₄ solution untilreaching pH 2. The aqueous solution was then extracted several timeswith diethyl ether and ethyl acetate. The aqueous solution was furtherextracted with ethyl acetate using a Kutscher-Steudel apparatus(continuous extraction). The combined organic phases were dried (sodiumsulfate) an concentrated in vacuo to yield the title compound as a whitesolid (2.1 g).

(b) 1,2,4-Trifluoro-5-methanesulfonyl-benzene

To 2,4,5-trifluoro-benzenesulfinic acid (2.0 g) in DMF (17 mL) was added4.3 g of potassium carbonate, and the reaction mixture was stirred for 5minutes before methyl iodide (2.2 mL) was added. The reaction mixturewas then stirred at room temperature for 60 hours. After such time,water (30 mL) was poured onto the reaction mixture, and the reactionmixture was extracted with diethylether several times. The combinedorganic phases were dried with sodium sulfate, and the remaining mixturewas distilled to yield the title compound as a light yellow oil (2.1 g).

(c) 1-(2,5-Difluoro-4-methanesulfonyl-phenyl)-piperazinetrifluoro-acetic acid

The title compound was obtained in analogy to example 2.7 using1,2,4-Trifluoro-5-methanesulfonyl-benzene. MS (m/e): 277.1 (M+H⁺).

EXAMPLE 2.21 Preparation of1-(3,5-Difluoro-4-methanesulfonyl-phenyl)-piperazine trifluoro-aceticacid

Compound 2.21 was prepared in analogy to compound 2.20 using2,4,6-trifluoro-benzenesulfonyl chloride [172326-59-9]. MS (m/e): 277.1(M+H⁺).

EXAMPLE 2.22 Preparation of5-Methanesulfonyl-2-(2,2,3,3-tetrafluoro-propoxy)-benzoic acid

Compound 2.22 was prepared in analogy to compound 2.18 using2,2,3,3-tetrafluoro-1-propyl triflate. MS (m/e): 329.1 (M−H).

EXAMPLE 2.23 Preparation of1-(2,6-Difluoro-4-methanesulfonyl-phenyl)-piperazine trifluoro-aceticacid

Compound 2.23 was prepared in analogy to compound 2.20 using3,4,5-trifluoro-benzenesulfonyl chloride [351003-43-5]. MS (m/e): 277.1(M+H⁺).

EXAMPLE 2.24 Preparation of4-Piperazin-1-yl-6-trifluoromethyl-pyrimidine trifluoro-acetic acid

Compound 2.24 was prepared in analogy to compound 2.7 using4-chloro-6-trifluoromethyl-pyrimidine [37552-81-1]. MS (m/e): 233.1(M+H⁺).

EXAMPLE 2.25 Preparation of2-Piperazin-1-yl-5-trifluoromethyl-pyrimidine

(a) 2-(4-Benzyl-piperazin-1-yl)-5-trifluoromethyl-pyrimidine

To a solution of(3-Dimethylamino-2-trifluoromethyl-allylidene)-dimethyl-ammoniumchloride ([176214-18-9], 0.60 g) in acetonitrile (10 mL) was added4-Benzyl-piperazine-1-carboxamidine hydrochloride ([7773-69-5], 0.66 g)and triethylamine (0.87 mL), and the reaction mixture was stirred for 3hours at room temperature. After such time, the reaction mixture wasconcentrated in vacuo and purified by column chromatography to yield thetitle compound as a light yellow solid (0.79 g). MS (m/e): 323.4 (M+H⁺).

(b) 2-Piperazin-1-yl-5-trifluoromethyl-pyrimidine

To a solution of2-(4-Benzyl-piperazin-1-yl)-5-trifluoromethyl-pyrimidine (0.63 g) inmethanol was added Palladium-C (Degussa E101N; 5%), and the reactionmixture was heated at 60° C. under hydrogen atmosphere. The reactionmixture was then allowed to cool down to room temperature, the catalystwas filtered off, and solvent was removed in vacuo to yield the titlecompound as a colorless solid (0.41 g). MS (m/e): 233.1 (M+H⁺).

In analogy to Example 5 compounds 108 to 280 of the following table wereprepared from the acid derivatives and piperazine derivatives:

Expl. MW found No. Systematic Name Starting materials (MH⁺) 108[2-(4-Fluoro-phenoxy)- 1-(4-trifluoromethyl- 490.5 5-nitro-phenyl]-phenyl)piperazine and 2-(4- [4-(4-trifluoromethyl- fluorophenoxy)-5-phenyl)-piperazin-1-yl]- nitrobenzoic acid methanone (compound 2.6) 1092,3-Difluoro-4-[4-(2- 2,3-Difluoro-4-piperazin-1- 464.3 isopropoxy-5-yl-benzonitrile-trifluoro- methanesulfonyl- acetic acid (compound 2.7)benzoyl)-piperazin-1-yl]- and 2-Isopropoxy-5- benzonitrilemethanesulfonyl-benzoic acid (compound 1.2) 110 2,5-Difluoro-4-[4-(2-2,5-Difluoro-4-piperazin-1- 464.1 isopropoxy-5-yl-benzonitrile-trifluoro- methanesulfonyl- acetic acid (compound 2.8)benzoyl)-piperazin-1-yl]- and 2-Isopropoxy-5- benzonitrilemethanesulfonyl-benzoic acid (compound 1.2) 111 3-[4-(4-Cyano-3-fluoro-2-Fluoro-4-piperazin-1-yl 487.1 phenyl)-piperazine-1- benzonitrile (WO9808835) carbonyl]-N-methyl-4- and 5-Methylsulfamoyl-2-trifluoromethoxy- trifluoromethoxy-benzoic benzenesulfonamide acid(compound 2.9) 112 3-Fluoro-4-{4-[5- 3-Fluoro-4-piperazin-1-yl- 500.3methanesulfonyl-2- benzonitrile (WO9625414) (3,3,3-trifluoro- and5-Methanesulfonyl-2- propoxy)-benzoyl]- (3,3,3-trifluoro-propoxy)-piperazin-1-yl}-benzonitrile benzoic acid (compound 2.10) 113 4-{4-[5-4-Piperazin-1-yl- 482.3 Methanesulfonyl-2- benzonitrile (commercial)(3,3,3-trifluoro- and 5-Methanesulfonyl-2- propoxy)-benzoyl]-(3,3,3-trifluoro-propoxy)- piperazin-1-yl}-benzonitrile benzoic acid(compound 2.10) 114 2-Fluoro-4-{4-[5- 2-Fluoro-4-piperazin-1-yl- 500.3methanesulfonyl-2- benzonitrile (WO 9808835) (3,3,3-trifluoro- and5-Methanesulfonyl-2- propoxy)-benzoyl]- (3,3,3-trifluoro-propoxy)-piperazin-1-yl}-benzonitrile benzoic acid (compound 2.10) 115[5-Methanesulfonyl-2- 1-(4-Trifluoromethyl- 525.2 (3,3,3-trifluoro-phenyl)-piperazine propoxy)-phenyl]-[4-(4- (commercial) and 5-trifluoromethyl-phenyl)- Methanesulfonyl-2-(3,3,3-piperazin-1-yl]-methanone trifluoro-propoxy)-benzoic acid (compound2.10) 116 [4-(3-Fluoro-4- 1-(3-Fluoro-4- 543.3 trifluoromethyl-phenyl)-trifluoromethyl-phenyl)- piperazin-1-yl]-[5- piperazine (compound 5.1)methanesulfonyl-2- and 5-Methanesulfonyl-2- (3,3,3-trifluoro-(3,3,3-trifluoro-propoxy)- propoxy)-phenyl]- benzoic acid (compound2.10) methanone 117 [4-(2-Fluoro-4- 1-(2-Fluoro-4- 543.2trifluoromethyl-phenyl)- trifluoromethyl-phenyl)- piperazin-1-yl]-[5-piperazine (compound methanesulfonyl-2- 1.1) and 5-Methane-(3,3,3-trifluoro- sulfonyl-2-(3,3,3-trifluoro- propoxy)-phenyl]-propoxy)-benzoic acid methanone (compound 2.10) 118 1-(3-Fluoro-4-{4-[5-1-(3-Fluoro-4-piperazin-1- 517.3 methanesulfonyl-2- yl-phenyl)-ethanone(3,3,3-trifluoro- (WO9714690) and 5- propoxy)-benzoyl]-Methanesulfonyl-2-(3,3,3- piperazin-1-yl}-phenyl)-trifluoro-propoxy)-benzoic ethanone acid (compound 2.10) 119[4-(2-Fluoro-4- 1-(2-Fluoro-4- 553.2 methanesulfonyl-methanesulfonyl-phenyl)- phenyl)-piperazin-1-yl]- piperazine(commercial) [5-methanesulfonyl-2- and 5-Methanesulfonyl-2-(3,3,3-trifluoro- (3,3,3-trifluoro-propoxy)- propoxy)-phenyl]- benzoicacid (compound 2.10) methanone 120 4-{4-[5- 4-Piperazin-1-yl- 470.0Methanesulfonyl-2- benzonitrile (commercial) (tetrahydro-pyran-4- and5-Methanesulfonyl-2- yloxy)-benzoyl]- (tetrahydro-pyran-4-yloxy)-piperazin-1-yl}- benzoic acid (compound 2.11) benzonitrile 1212-Fluoro-4-{4-[5- 2-Fluoro-4-piperazin-1-yl- 488.1 methanesulfonyl-2-benzonitrile (WO 9808835) (tetrahydro-pyran-4- and 5-Methanesulfonyl-2-yloxy)-benzoyl]- (tetrahydro-pyran-4-yloxy)- piperazin-1-yl}- benzoicacid (compound 2.11) benzonitrile 122 3-Fluoro-4-{4-[5-3-Fluoro-4-piperazin-1-yl- 488.0 methanesulfonyl-2- benzonitrile(WO9625414) (tetrahydro-pyran-4- and 5-Methanesulfonyl-2-yloxy)-benzoyl]- (tetrahydro-pyran-4-yloxy)- piperazin-1-yl}- benzoicacid (compound 2.11) benzonitrile 123 [5-Methanesulfonyl-2-1-(4-Trifluoromethyl- 513.3 (tetrahydro-pyran-4- phenyl)-piperazineyloxy)-phenyl]-[4-(4- (commercial) and 5- trifluoromethyl-phenyl)-Methanesulfonyl-2- piperazin-1-yl]- (tetrahydro-pyran-4-yloxy)-methanone benzoic acid (compound 2.11) 124 [4-(3-Fluoro-4-1-(3-Fluoro-4- 531.0 trifluoromethyl-phenyl)- trifluoromethyl-phenyl)-piperazin-1-yl]-[5- piperazine (compound 5.1) methanesulfonyl-2- and5-Methanesulfonyl-2- (tetrahydro-pyran-4- (tetrahydro-pyran-4-yloxy)-yloxy)-phenyl]- benzoic acid (compound 2.11) methanone 125[4-(2-Fluoro-4- 1-(2-Fluoro-4- 531.2 trifluoromethyl-phenyl)-trifluoromethyl-phenyl)- piperazin-1-yl]-[5- piperazine (compoundmethanesulfonyl-2- 1.1) and 5- (tetrahydro-pyran-4- Methanesulfonyl-2-yloxy)-phenyl]- (tetrahydro-pyran-4-yloxy)- methanone benzoic acid(compound 2.11) 126 1-(3-Fluoro-4-{4-[5- 1-(3-Fluoro-4-piperazin-1-505.1 methanesulfonyl-2- yl-phenyl)-ethanone (tetrahydro-pyran-4-(WO9714690) and 5- yloxy)-benzoyl]- Methanesulfonyl-2-piperazin-1-yl}-phenyl)- (tetrahydro-pyran-4-yloxy)- ethanone benzoicacid (compound 2.11) 127 [4-(2-Fluoro-4- 1-(2-Fluoro-4- 541.3methanesulfonyl- methanesulfonyl-phenyl)- phenyl)-piperazin-1-yl]-piperazine (commercial) [5-methanesulfonyl-2- and 5-Methanesulfonyl-2-(tetrahydro-pyran-4- (tetrahydro-pyran-4-yloxy)- yloxy)-phenyl]- benzoicacid (compound 2.11) methanone 128 2,3-Difluoro-4-[4-(2-2,3-Difluoro-4-piperazin-1- 478.1 isobutoxy-5-yl-benzonitrile-trifluoro- methanesulfonyl- acetic acid (compound 2.7)benzoyl)-piperazin-1-yl]- and 2-Isobutoxy-5- benzonitrilemethanesulfonyl-benzoic acid (compound 1.3) 129 4-[4-(2-2,3-Difluoro-4-piperazin-1- 476.3 Cyclopropylmethoxy-5-yl-benzonitrile-trifluoro- methanesulfonyl- acetic acid (compound 2.7)benzoyl)-piperazin-1-yl]- and 2-Cyclopropylmethoxy-2,3-difluoro-benzonitrile 5-methanesulfonyl-benzoic acid (compound 1.4)130 2,3-Difluoro-4-{4-[5- 2,3-Difluoro-4-piperazin-1- 506.4methanesulfonyl-2- yl-benzonitrile-trifluoro- (tetrahydro-pyran-4-acetic acid (compound 2.7) yloxy)-benzoyl]- and 5-Methanesulfonyl-2-piperazin-1-yl}- (tetrahydro-pyran-4-yloxy)- benzonitrile benzoic acid(compound 2.11) 131 4-[4-(2-Cyclopentyloxy- 2,3-Difluoro-4-piperazin-1-490.5 5-methanesulfonyl- yl-benzonitrile-trifluoro-benzoyl)-piperazin-1-yl]- acetic acid (compound 2.7)2,3-difluoro-benzonitrile and 2-Cyclopentyloxy-5-methanesulfonyl-benzoic acid (compound 1.6) 132 2,5-Difluoro-4-[4-(2-2,5-Difluoro-4-piperazin-1- 478.4 isobutoxy-5-yl-benzonitrile-trifluoro- methanesulfonyl- acetic acid (compound 2.8)benzoyl)-piperazin-1-yl]- and 2-Isobutoxy-5- benzonitrilemethanesulfonyl-benzoic acid (compound 1.3) 133 4-[4-(2-2,5-Difluoro-4-piperazin-1- 476.3 Cyclopropylmethoxy-5-yl-benzonitrile-trifluoro- methanesulfonyl- acetic acid (compound 2.8)benzoyl)-piperazin-1-yl]- and 2-Cyclopropylmethoxy-2,5-difluoro-benzonitrile 5-methanesulfonyl-benzoic acid (compound 1.4)134 2,5-Difluoro-4-{4-[5- 2,5-Difluoro-4-piperazin-1- 506.4methanesulfonyl-2- yl-benzonitrile-trifluoro- (tetrahydro-pyran-4-acetic acid (compound 2.8) yloxy)-benzoyl]- and 5-Methanesulfonyl-2-piperazin-1-yl}- (tetrahydro-pyran-4-yloxy)- benzonitrile benzoic acid(compound 2.11) 135 4-[4-(2-Cyclopentyloxy- 2,5-Difluoro-4-piperazin-1-490.5 5-methanesulfonyl- yl-benzonitrile-trifluoro-benzoyl)-piperazin-1-yl]- acetic acid (compound 2.8)2,5-difluoro-benzonitrile and 2-Cyclopentyloxy-5- methanesulfonyl-benzoic acid (compound 1.6) 136 4-[4-(2- 4-Piperazin-1-yl- 454.6Cyclobutylmethoxy-5- benzonitrile (commercial) methanesulfonyl- and2-Cyclobutylmethoxy- benzoyl)-piperazin-1-yl]- 5-methanesulfonyl-benzoicbenzonitrile acid (compound 2.12) 137 4-[4-(2-2-Fluoro-4-piperazin-1-yl- 472.3 Cyclobutylmethoxy-5- benzonitrile (WO9808835) methanesulfonyl- and 2-Cyclobutylmethoxy-benzoyl)-piperazin-1-yl]- 5-methanesulfonyl-benzoic2-fluoro-benzonitrile acid (compound 2.12) 138 4-[4-(2-3-Fluoro-4-piperazin-1-yl- 472.3 Cyclobutylmethoxy-5- benzonitrile(WO9625414) methanesulfonyl- and 2-Cyclobutylmethoxy-benzoyl)-piperazin-1-yl]- 5-methanesulfonyl-benzoic3-fluoro-benzonitrile acid (compound 2.12) 139 (2-Cyclobutylmethoxy-5-1-(4-Trifluoromethyl- 497.3 methanesulfonyl- phenyl)-piperazinephenyl)-[4-(4- (commercial) and 2- trifluoromethyl-phenyl)-Cyclobutylmethoxy-5- piperazin-1-yl]- methanesulfonyl-benzoic methanoneacid (compound 2.12) 140 (2-Cyclobutylmethoxy-5- 1-(3-Fluoro-4- 515.4methanesulfonyl- trifluoromethyl-phenyl)- phenyl)-[4-(3-fluoro-4-piperazine (compound 5.1) trifluoromethyl-phenyl)- and2-Cyclobutylmethoxy- piperazin-1-yl]- 5-methanesulfonyl-benzoicmethanone acid (compound 2.12) 141 (2-Cyclobutylmethoxy-5-1-(2-Fluoro-4- 515.4 methanesulfonyl- trifluoromethyl-phenyl)-phenyl)-[4-(2-fluoro-4- piperazine (compound trifluoromethyl-phenyl)-1.1) and 2- piperazin-1-yl]- Cyclobutylmethoxy-5- methanonemethanesulfonyl-benzoic acid (compound 2.12) 142 1-{4-[4-(2-1-(3-Fluoro-4-piperazin-1- 489.5 Cyclobutylmethoxy-5-yl-phenyl)-ethanone methanesulfonyl- (WO9714690) and 2-benzoyl)-piperazin-1-yl]- Cyclobutylmethoxy-5- 3-fluoro-phenyl}-methanesulfonyl-benzoic ethanone acid (compound 2.12) 143(2-Cyclobutylmethoxy-5- 1-(2-Fluoro-4- 525.3 methanesulfonyl-methanesulfonyl-phenyl)- phenyl)-[4-(2-fluoro-4- piperazine (commercial)methanesulfonyl- and 2-Cyclobutylmethoxy- phenyl)-piperazin-1-yl]-5-methanesulfonyl-benzoic methanone acid (compound 2.12) 144 2-[4-(2-2-Piperazin-1-yl-5- 522.4 Cyclobutylmethoxy-5-trifluoromethyl-benzonitrile methanesulfonyl- (compound 5.2) and 2-benzoyl)-piperazin-1-yl]- Cyclobutylmethoxy-5- 5-trifluoromethyl-methanesulfonyl-benzoic benzonitrile acid (compound 2.12) 145 4-[4-(2-2,3-Difluoro-4-piperazin-1- 490.5 Cyclobutylmethoxy-5-yl-benzonitrile-trifluoro- methanesulfonyl- acetic acid (compound 2.7)benzoyl)-piperazin-1-yl]- and 2-Cyclobutylmethoxy-2,3-difluoro-benzonitrile 5-methanesulfonyl-benzoic acid (compound 2.12)146 4-[4-(2- 2,5-Difluoro-4-piperazin-1- 490.5 Cyclobutylmethoxy-5-yl-benzonitrile-trifluoro- methanesulfonyl- acetic acid (compound 2.8)benzoyl)-piperazin-1-yl]- and 2-Cyclobutylmethoxy-2,5-difluoro-benzonitrile 5-methanesulfonyl-benzoic acid (compound 2.12)147 4-[4-(2- 3,5-Difluoro-4-piperazin-1- 490.5 Cyclobutylmethoxy-5-yl-benzonitrile trifluoro methanesulfonyl- acetic acid (compound 2.13)benzoyl)-piperazin-1-yl]- and 2-Cyclobutylmethoxy-3,5-difluoro-benzonitrile 5-methanesulfonyl-benzoic acid (compound 2.12)148 4-[4-(2- 2,6-Difluoro-4-piperazin-1- 490.5 Cyclobutylmethoxy-5-yl-benzonitrile trifluoro- methanesulfonyl- acetic acid (compound 2.14)benzoyl)-piperazin-1-yl]- and 2-Cyclobutylmethoxy-2,6-difluoro-benzonitrile 5-methanesulfonyl-benzoic acid (compound 2.12)149 2,5-Difluoro-4-{4-[5- 2,5-Difluoro-4-piperazin-1- 504.0methanesulfonyl-2- yl-benzonitrile-trifluoro- (2,2,2-trifluoro-ethoxy)-acetic acid (compound 2.8) benzoyl]-piperazin-1-yl}- and5-Methanesulfonyl-2- benzonitrile (2,2,2-trifluoro-ethoxy)- benzoic acid(compound 1.5) 150 2,3-Difluoro-4-{4-[5- 2,3-Difluoro-4-piperazin-1-504.1 methanesulfonyl-2- yl-benzonitrile-trifluoro-(2,2,2-trifluoro-ethoxy)- acetic acid (compound 2.7)benzoyl]-piperazin-1-yl}- and 5-Methanesulfonyl-2- benzonitrile(2,2,2-trifluoro-ethoxy)- benzoic acid (compound 1.5) 1512,5-Difluoro-4-[4-(5- 2,5-Difluoro-4-piperazin-1- 490.0methanesulfonyl-2- yl-benzonitrile-trifluoro- trifluoromethoxy- aceticacid (compound 2.8) benzoyl)-piperazin-1-yl]- and 5-Methanesulfonyl-2-benzonitrile trifluoromethoxy-benzoic acid (compound 2.15) 152 4-[4-(5-4-Piperazin-1-yl- 454.3 Methanesulfonyl-2- benzonitrile (commercial)trifluoromethoxy- and 5-Methanesulfonyl-2- benzoyl)-piperazin-1-yl]-trifluoromethoxy-benzoic benzonitrile acid (compound 2.15) 1532-Fluoro-4-[4-(5- 2-Fluoro-4-piperazin-1-yl- 472.1 methanesulfonyl-2-benzonitrile (WO 9808835) trifluoromethoxy- and 5-Methanesulfonyl-2-benzoyl)-piperazin-1-yl]- trifluoromethoxy-benzoic benzonitrile acid(compound 2.15) 154 3-Fluoro-4-[4-(5- 3-Fluoro-4-piperazin-1-yl- 472.0methanesulfonyl-2- benzonitrile (WO9625414) trifluoromethoxy- and5-Methanesulfonyl-2- benzoyl)-piperazin-1-yl]- trifluoromethoxy-benzoicbenzonitrile acid (compound 2.15) 155 (5-Methanesulfonyl-2-1-(4-Trifluoromethyl- 514.2 trifluoromethoxy- phenyl)-piperazine (M +NH₄ ⁺) phenyl)-[4-(4- (commercial) and 5- trifluoromethyl-phenyl)-Methanesulfonyl-2- piperazin-1-yl]- trifluoromethoxy-benzoic methanoneacid (compound 2.15) 156 [4-(3-Fluoro-4- 1-(3-Fluoro-4- 532.2trifluoromethyl-phenyl)- trifluoromethyl-phenyl)- (M + NH₄ ⁺)piperazin-1-yl]-(5- piperazine (compound 5.1) methanesulfonyl-2- and5-Methanesulfonyl-2- trifluoromethoxy- trifluoromethoxy-benzoicphenyl)-methanone acid (compound 2.15) 157 [4-(2-Fluoro-4-1-(2-Fluoro-4- 515.3 trifluoromethyl-phenyl)- trifluoromethyl-phenyl)-piperazin-1-yl]-(5- piperazine (compound methanesulfonyl-2- 1.1) and 5-trifluoromethoxy Methanesulfonyl-2- phenyl)-methanonetrifluoromethoxy-benzoic acid (compound 2.15) 158 2,3-Difluoro-4-[4-(5-2,3-Difluoro-4-piperazin-1- 507.4 methanesulfonyl-2-yl-benzonitrile-trifluoro- (M + NH₄ ⁺) trifluoromethoxy- acetic acid(compound 2.7) benzoyl)-piperazin-1-yl]- and 5-Methanesulfonyl-2-benzonitrile trifluoromethoxy-benzoic acid (compound 2.15) 1593,5-Difluoro-4-[4-(5 3,5-Difluoro-4-piperazin-1- 507.3methanesulfonyl-2- yl-benzonitrile trifluoro- (M + NH⁴⁺)trifluoromethoxy- acetic acid (compound 2.13) benzoyl)-piperazin-1-yl]-and 5-Methanesulfonyl-2- benzonitrile trifluoromethoxy-benzoic acid(compound 2.15) 160 2,6-Difluoro-4-[4-(5- 2,6-Difluoro-4-piperazin-1-507.4 methanesulfonyl-2- yl-benzonitrile trifluoro- (M + NH⁴⁺)trifluoromethoxy- acetic acid (compound 2.14) benzoyl)-piperazin-1-yl]-and 5-Methanesulfonyl-2- benzonitrile trifluoromethoxy-benzoic acid(compound 2.15) 161 [4-(2-Fluoro-4- 1-(2-Fluoro-4- 542.0methanesulfonyl- methanesulfonyl-phenyl)- (M + NH⁴⁺)phenyl)-piperazin-1-yl]- piperazine (commercial) (5-methanesulfonyl-2-and 5-Methanesulfonyl-2- trifluoromethoxy- trifluoromethoxy-benzoicphenyl)-methanone acid (compound 2.15) 162 2-[4-(5- 2-Piperazin-1-yl-5-539.2 Methanesulfonyl-2- trifluoromethyl-benzonitrile (M + NH⁴⁺)trifluoromethoxy- (compound 5.2)and 5- benzoyl)-piperazin-1-yl]-Methanesulfonyl-2- 5-trifluoromethyl- trifluoromethoxy-benzoicbenzonitrile acid (compound 2.15) 163 3,5-Difluoro-4-[4-(2-3,5-Difluoro-4-piperazin-1- 464.1 isopropoxy-5- yl-benzonitriletrifluoro- methanesulfonyl- acetic acid (compound 2.13)benzoyl)-piperazin-1-yl]- and 2-Isopropoxy-5- benzonitrilemethanesulfonyl-benzoic acid (compound 1.2) 164 3,5-Difluoro-4-[4-(2-3,5-Difluoro-4-piperazin-1- 478.0 isobutoxy-5- yl-benzonitriletrifluoro- methanesulfonyl- acetic acid (compound 2.13)benzoyl)-piperazin-1-yl]- and 2-Isobutoxy-5- benzonitrilemethanesulfonyl-benzoic acid (compound 1.3) 165 4-[4-(2-3,5-Difluoro-4-piperazin-1- 476.1 Cyclopropylmethoxy-5- yl-benzonitriletrifluoro- methanesulfonyl- acetic acid (compound 2.13)benzoyl)-piperazin-1-yl]- and 2-Cyclopropylmethoxy-3,5-difluoro-benzonitrile 5-methanesulfonyl-benzoic acid (compound 1.4)166 3,5-Difluoro-4-{4-[5- 3,5-Difluoro-4-piperazin-1- 504.1methanesulfonyl-2- yl-benzonitrile trifluoro- (2,2,2-trifluoro-ethoxy)-acetic acid (compound 2.13) benzoyl]-piperazin-1-yl}- and5-Methanesulfonyl-2- benzonitrile (2,2,2-trifluoro-ethoxy)- benzoic acid(compound 1.5) 167 4-[4-(2-Cyclopentyloxy- 3,5-Difluoro-4-piperazin-1-490.3 5-methanesulfonyl- yl-benzonitrile trifluoro-benzoyl)-piperazin-1-yl]- acetic acid (compound 2.13)3,5-difluoro-benzonitrile and 2-Cyclopentyloxy-5- methanesulfonyl-benzoic acid (compound 1.6) 168 2,6-Difluoro-4-[4-(2-2,6-Difluoro-4-piperazin-1- 481.1 isopropoxy-5- yl-benzonitriletrifluoro- (M + NH₄ ⁺) methanesulfonyl- acetic acid (compound 2.14)benzoyl)-piperazin-1-yl]- and 2-Isopropoxy-5- benzonitrilemethanesulfonyl-benzoic acid (compound 1.2) 169 2,6-Difluoro-4-[4-(2-2,6-Difluoro-4-piperazin-1- 495.0 isobutoxy-5- yl-benzonitriletrifluoro- (M + NH₄ ⁺) methanesulfonyl- acetic acid (compound 2.14)benzoyl)-piperazin-1-yl]- and 2-Isobutoxy-5- benzonitrilemethanesulfonyl-benzoic acid (compound 1.3) 170 4-[4-(2-2,6-Difluoro-4-piperazin-1- 493.0 Cyclopropylmethoxy-5- yl-benzonitriletrifluoro- (M + NH₄ ⁺) methanesulfonyl- acetic acid (compound 2.14)benzoyl)-piperazin-1-yl]- and 2-Cyclopropylmethoxy-2,6-difluoro-benzonitrile 5-methanesulfonyl-benzoic acid (compound 1.4)171 2,6-Difluoro-4-{4-[5- 2,6-Difluoro-4-piperazin-1- 521.3methanesulfonyl-2- yl-benzonitrile trifluoro- (M + NH₄ ⁺)(2,2,2-trifluoro-ethoxy)- acetic acid (compound 2.14)benzoyl]-piperazin-1-yl}- and 5-Methanesulfonyl-2- benzonitrile(2,2,2-trifluoro-ethoxy)- benzoic acid (compound 1.5) 1724-[4-(2-Cyclopentyloxy- 2,6-Difluoro-4-piperazin-1- 507.35-methanesulfonyl- yl-benzonitrile trifluoro- (M + NH₄ ⁺)benzoyl)-piperazin-1-yl]- acetic acid (compound 2.14)2,6-difluoro-benzonitrile and 2-Cyclopentyloxy-5- methanesulfonyl-benzoic acid (compound 1.6) 173 2,4-Difluoro-6-[4-(2-2,4-Difluoro-6-piperazin-1- 581.4 isopropoxy-5- yl-benzonitriletrifluoro- (M + NH₄ ⁺) methanesulfonyl- acetic acid (compound 2.16)benzoyl)-piperazin-1-yl]- and 2-Isopropoxy-5- benzonitrilemethanesulfonyl-benzoic acid (compound 1.2) 174 2-Fluoro-4-{4-[2-(2-2-Fluoro-4-piperazin-1-yl- 482.3 fluoro-1-fluoromethyl- benzonitrile (WO9808835) ethoxy)-5- and 2-(2-Fluoro-1- methanesulfonyl-fluoromethyl-ethoxy)-5- benzoyl]-piperazin-1-yl}-methanesulfonyl-benzoic benzonitrile acid (compound 2.17) 1753-Fluoro-4-{4-[2-(2- 3-Fluoro-4-piperazin-1-yl- 482.4fluoro-1-fluoromethyl- benzonitrile (WO9625414) ethoxy)-5- and2-(2-Fluoro-1- methanesulfonyl- fluoromethyl-ethoxy)-5-benzoyl]-piperazin-1-yl}- methanesulfonyl-benzoic benzonitrile acid(compound 2.17) 176 2,3-Difluoro-4{4-[2-(2- 2,3-Difluoro-4-piperazin-1-500.3 fluoro-1-fluoromethyl- yl-benzonitrile-trifluoro- ethoxy)-5-acetic acid (compound 2.7) methanesulfonyl- and 2-(2-Fluoro-1-benzoyl]-piperazin-1-yl}- fluoromethyl-ethoxy)-5- benzonitrilemethanesulfonyl-benzoic acid (compound 2.17) 1772,5-Difluoro-4-{4-[2-(2- 2,5-Difluoro-4-piperazin-1- 500.3fluoro-1-fluoromethyl- yl-benzonitrile-trifluoro- ethoxy)-5- acetic acid(compound 2.8) methanesulfonyl- and 2-(2-Fluoro-1-benzoyl]-piperazin-1-yl}- fluoromethyl-ethoxy)-5- benzonitrilemethanesulfonyl-benzoic acid (compound 2.17) 1783-5-Difluoro-4-{4-[2-(2- 3,5-Difluoro-4-piperazin-1- 500.3fluoro-1-fluoromethyl- yl-benzonitrile trifluoro- ethoxy)-5- acetic acid(compound 2.13) methanesulfonyl- and 2-(2-Fluoro-1-benzoyl]-piperazin-1-yl}- fluoromethyl-ethoxy)-5- benzonitrilemethanesulfonyl-benzoic acid (compound 2.17) 1792,6-Difluoro-4-{4-[2-(2- 2,6-Difluoro-4-piperazin-1- 500.3fluoro-1-fluoromethyl- yl-benzonitrile trifluoro- ethoxy)-5- acetic acid(compound 2.14) methanesulfonyl- and 2-(2-Fluoro-1-benzoyl]-piperazin-1-yl}- fluoromethyl-ethoxy)-5- benzonitrilemethanesulfonyl-benzoic acid (compound 2.17) 180 2-Fluoro-4-{4-[5-2-Fluoro-4-piperazin-1-yl 536.3 methanesulfonyl-2- benzonitrile (WO9808835) (2,2,3,3,3-pentafluoro- and 5-Methanesulfonyl-2-propoxy)-benzoyl]- (2,2,3,3,3-pentafluoro- piperazin-1-yl}-propoxy)-benzoic acid benzonitrile (compound 2.18) 181 3-Fluoro-4-{4-[5-3-Fluoro-4-piperazin-1-yl- 536.3 methanesulfonyl-2- benzonitrile(WO9625414) (2,2,3,3,3-pentafluoro- and 5-Methanesulfonyl-2-propoxy)-benzoyl]- (2,2,3,3,3-pentafluoro- piperazin-1-yl}-propoxy)-benzoic acid benzonitrile (compound 2.18) 182[5-Methanesulfonyl-2- 1-(4-Trifluoromethyl- 561.3(2,2,3,3,3-pentafluoro- phenyl)-piperazine propoxy)-phenyl]-[4-(4-(commercial) and 5- trifluoromethyl-phenyl)- Methanesulfonyl-2-piperazin-1-yl]- (2,2,3,3,3-pentafluoro- methanone propoxy)-benzoic acid(compound 2.18) 183 [4-(3-Fluoro-4- 1-(3-Fluoro-4- 579.0trifluoromethyl-phenyl)- trifluoromethyl-phenyl)- piperazin-1-yl]-[5-piperazine (compound 5.1) methanesulfonyl-2- and 5-Methanesulfonyl-2-(2,2,3,3,3-pentafluoro- (2,2,3,3,3-pentafluoro- propoxy)-phenyl]-propoxy)-benzoic acid methanone (compound 2.18) 1842,3-Difluoro-4-{4-[5- 2,3-Difluoro-4-piperazin-1- 554.0methanesulfonyl-2- yl-benzonitrile-trifluoro- (2,2,3,3,3-pentafluoro-acetic acid (compound 2.7) propoxy)-benzoyl]- and 5-Methanesulfonyl-2-piperazin-1-yl}- (2,2,3,3,3-pentafluoro- benzonitrile propoxy)-benzoicacid (compound 2.18) 185 2,5-Difluoro-4-{4-[5-2,5-Difluoro-4-piperazin-1- 554.0 methanesulfonyl-2-yl-benzonitrile-trifluoro- (2,2,3,3,3-pentafluoro- acetic acid (compound2.8) propoxy)-benzoyl]- and 5-Methanesulfonyl-2- piperazin-1-yl}-(2,2,3,3,3-pentafluoro- benzonitrile propoxy)-benzoic acid (compound2.18) 186 3,5-Difluoro-4-{4-[5- 3,5-Difluoro-4-piperazin-1- 554.0methanesulfonyl-2- yl-benzonitrile trifluoro- (2,2,3,3,3-pentafluoro-acetic acid (compound 2.13) propoxy)-benzoyl]- and 5-Methanesulfonyl-2-piperazin-1-yl}- (2,2,3,3,3-pentafluoro- benzonitrile propoxy)-benzoicacid (compound 2.18) 187 2,6-Difluoro-4-{4-[5-2,6-Difluoro-4-piperazin-1- 571.2 methanesulfonyl-2- yl-benzonitriletrifluoro- (M + NH₄ ⁺) (2,2,3,3,3-pentafluoro- acetic acid (compound2.14) propoxy)-benzoyl]- and 5-Methanesulfonyl-2- piperazin-1-yl}-(2,2,3,3,3-pentafluoro- benzonitrile propoxy)-benzoic acid (compound2.18) 188 [4-(2-Fluoro-4- 1-(2-Fluoro-4- 589.3 methanesulfonyl-methanesulfonyl-phenyl)- phenyl)-piperazin-1-yl]- piperazine(commercial) [5-methanesulfonyl-2- and 5-Methanesulfonyl-2-(2,2,3,3,3-pentafluoro- (2,2,3,3,3-pentafluoro- propoxy)-phenyl]-propoxy)-benzoic acid methanone (compound 2.18) 189 4-{4-[2-(2-Fluoro-1-4-Piperazin-1-yl- 464.1 fluoromethyl-ethoxy)-5- benzonitrile(commercial) methanesulfonyl- and 2-(2-Fluoro-1-benzoyl]-piperazin-1-yl}- fluoromethyl-ethoxy)-5- benzonitrilemethanesulfonyl-benzoic acid (compound 2.17) 190 [2-(2-Fluoro-1-1-(4-Trifluoromethyl- 507.3 fluoromethyl-ethoxy)-5- phenyl)-piperazinemethanesulfonyl- (commercial) and 2-(2- phenyl]-[4-(4-Fluoro-1-fluoromethyl- trifluoromethyl-phenyl)-ethoxy)-5-methanesulfonyl- piperazin-1-yl]- benzoic acid (compound 2.17)methanone 191 [2-(2-Fluoro-1- 1-(3-Fluoro-4- 525.2fluoromethyl-ethoxy)-5- trifluoromethyl-phenyl)- methanesulfonyl-piperazine (compound 5.1) phenyl]-[4-(3-fluoro-4- and 2-(2-Fluoro-1-trifluoromethyl-phenyl)- fluoromethyl-ethoxy)-5- piperazin-1-yl]-methanesulfonyl-benzoic methanone acid (compound 2.17) 192[2-(2-Fluoro-1- 1-(2-Fluoro-4- 525.0 fluoromethyl-ethoxy)-5-trifluoromethyl-phenyl)- methanesulfonyl- piperazine (compoundphenyl]-[4-(2-fluoro-4- 1.1) and 2-(2-Fluoro-1- trifluoromethyl-phenyl)-fluoromethyl-ethoxy)-5- piperazin-1-yl]- methanesulfonyl-benzoicmethanone acid (compound 2.17) 193 [2-(2-Fluoro-1- 1-(2-Fluoro-4- 535.3fluoromethyl-ethoxy)-5- methanesulfonyl-phenyl)- methanesulfonyl-piperazine (commercial) phenyl]-[4-(2-fluoro-4- and 2-(2-Fluoro-1-methanesulfonyl- fluoromethyl-ethoxy)-5- phenyl)-piperazin-1-yl]-methanesulfonyl-benzoic methanone acid (compound 2.17) 1942-{4-[2-(2-Fluoro-1- 2-Piperazin-1-yl-5- 532.2 fluoromethyl-ethoxy)-5-trifluoromethyl-benzonitrile methanesulfonyl- (compound 5.2) and 2-(2-benzoyl]-piperazin-1-yl}- Fluoro-1-fluoromethyl- 5-trifluoromethyl-ethoxy)-5-methanesulfonyl- benzonitrile benzoic acid (compound 2.17) 195[4-(2,3-Difluoro-4- 1-(2,3-Difluoro-4- 553.2 methanesulfonyl-methanesulfonyl-phenyl)- phenyl)-piperazin-1-yl]- piperazine (compound5.3) [2-(2-fluoro-1- and 2-(2-Fluoro-1- fluoromethyl-ethoxy)-5-fluoromethyl-ethoxy)-5- methanesulfonyl- methanesulfonyl-benzoicphenyl]-methanone acid (compound 2.17) 196 4-[4-(2-tert-Butoxy-5-2,3-Difluoro-4-piperazin-1- 478.3 methanesulfonyl-yl-benzonitrile-trifluoro- benzoyl)-piperazin-1-yl]- acetic acid(compound 2.7) 2,3-difluoro-benzonitrile and 2-tert-Butoxy-5-methanesulfonyl-benzoic acid (compound 2.19) 197 [4-(2,5-Difluoro-4-1-(2,5-Difluoro-4- 534.3 methanesulfonyl- methanesulfonyl-phenyl)- (M +NH₄ ⁺) phenyl)-piperazin-1-yl]- piperazine trifluoro-acetic(2-isopropoxy-5- acid (compound 2.20) and methanesulfonyl-2-Isopropoxy-5- phenyl)-methanone methanesulfonyl-benzoic acid (compound1.2) 198 [4-(3,5-Difluoro-4- 1-(3,5-Difluoro-4- 534.3 methanesulfonyl-methanesulfonyl-phenyl)- (M + NH₄ ⁺) phenyl)-piperazin-1-yl]- piperazinetrifluoro-acetic (2-isopropoxy-5- acid (compound 2.21) andmethanesulfonyl- 2-Isopropoxy-5- phenyl)-methanonemethanesulfonyl-benzoic acid (compound 1.2) 199 2-[4-(2-Isopropoxy-5-2-Piperazin-1-yl- 428.5 methanesulfonyl- benzonitrile (commercial)benzoyl)-piperazin-1-yl]- and 2-Isopropoxy-5- benzonitrilemethanesulfonyl-benzoic acid (compound 1.2) 200 [4-(2-Fluoro-phenyl)-1-(2-Fluoro-phenyl)- 421.3 piperazin-1-yl]-(2- piperazine (commercial)isopropoxy-5- and 2-Isopropoxy-5- methanesulfonyl-methanesulfonyl-benzoic phenyl)-methanone acid (compound 1.2) 201[4-(4-Chloro-phenyl)- 1-(4-Chloro-phenyl)- 437.3 piperazin-1-yl]-(2-piperazine (commercial) isopropoxy-5- and 2-Isopropoxy-5-methanesulfonyl- methanesulfonyl-benzoic phenyl)-methanone acid(compound 1.2) 202 5-Chloro-2-[4-(2- 5-Chloro-2-piperazin-1-yl- 462.1isopropoxy-5- benzonitrile (WO9625414) methanesulfonyl- and2-Isopropoxy-5- benzoyl)-piperazin-1-yl]- methanesulfonyl-benzoicbenzonitrile acid (compound 1.2) 203 [4-(4-Chloro-2-fluoro-1-(4-Chloro-2-fluoro- 455.4 phenyl)-piperazin-1-yl]- phenyl)-piperazine(2-isopropoxy-5- hydrochloride (commercial) methanesulfonyl- and2-Isopropoxy-5- phenyl)-methanone methanesulfonyl-benzoic acid (compound1.2) 204 [4-(4-Chloro-3- 1-(4-Chloro-3- 505.3 trifluoromethyl-phenyl)-trifluoromethyl-phenyl)- piperazin-1-yl]-(2- piperazine (commercial)isopropoxy-5- and 2-Isopropoxy-5- methanesulfonyl-methanesulfonyl-benzoic phenyl)-methanone acid (compound 1.2) 205[4-(3,4-Dichloro- 1-(3,4-Dichloro-phenyl)- 471.0phenyl)-piperazin-1-yl]- piperazine (commercial) (2-isopropoxy-5- and2-Isopropoxy-5- methanesulfonyl- methanesulfonyl-benzoicphenyl)-methanone acid (compound 1.2) 206 [4-(2-Fluoro-4-methyl-1-(2-Fluoro-4-methyl- 435.3 phenyl)-piperazin-1-yl]- phenyl)-piperazine(2-isopropoxy-5- (compound 5.4) and 2- methanesulfonyl- Isopropoxy-5-phenyl)-methanone methanesulfonyl-benzoic acid (compound 1.2) 207rac-2,3-Difluoro-4-{4-[5- 2,3-Difluoro-4-piperazin-1- 535.3methanesulfonyl-2- yl-benzonitrile-trifluoro- (M + NH₄ ⁺)(2,2,2-trifluoro-1- acetic acid (compound 2.7) methyl-ethoxy)- andrac-5-Methanesulfonyl- benzoyl]-piperazin-1-yl}-2-(2,2,2-trifluoro-1-methyl- benzonitrile ethoxy)-benzoic acid (compound3.1) 208 (2-Isopropoxy-5- 1-(4-Trifluoromethoxy- 487.3 methanesulfonyl-phenyl)-piperazine phenyl)-[4-(4- (WO03007954) and 2- trifluoromethoxy-Isopropoxy-5- phenyl)-piperazin-1-yl]- methanesulfonyl-benzoic methanoneacid (compound 1.2) 209 2-Fluoro-4-{4-[5- 2-Fluoro-4-piperazin-1-yl-535.3 methanesulfonyl-2- benzonitrile (WO 9808835) (M + NH₄ ⁺)(2,2,3,3-tetrafluoro- and 5-Methanesulfonyl-2- propoxy)-benzoyl]-(2,2,3,3-tetrafluoro- piperazin-1-yl}- propoxy)-benzoic acidbenzonitrile (compound 2.22) 210 3-Fluoro-4-{4-[5-3-Fluoro-4-piperazin-1-yl- 535.5 methanesulfonyl-2- benzonitrile(WO9625414) (M + NH₄ ⁺) (2,2,3,3-tetrafluoro- and 5-Methanesulfonyl-2-propoxy)-benzoyl]- (2,2,3,3-tetrafluoro- piperazin-1-yl}-propoxy)-benzoic acid benzonitrile (compound 2.22) 211[5-Methanesulfonyl-2- 1-(4-Trifluoromethyl- 560.3 (2,2,3,3-tetrafluoro-phenyl)-piperazine (M + NH₄ ⁺) propoxy)-phenyl]-[4-(4- (commercial) and5- trifluoromethyl-phenyl)- Methanesulfonyl-2-(2,2,3,3- piperazin-1-yl]-tetrafluoro-propoxy)- methanone benzoic acid (compound 2.22) 212[4-(2-Fluoro-4- 1-(2-Fluoro-4- 578.2 trifluoromethyl-phenyl)-trifluoromethyl-phenyl)- (M + NH₄ ⁺) piperazin-1-yl]-[5- piperazine(compound methanesulfonyl-2- 1.1) and 5- (2,2,3,3-tetrafluoro-Methanesulfonyl-2-(2,2,3,3- propoxy)-phenyl]- tetrafluoro-propoxy)-methanone benzoic acid (compound 2.22) 213 2,3-Difluoro-4-{4-[5-2,3-Difluoro-4-piperazin-1- 553.2 methanesulfonyl-2-yl-benzonitrile-trifluoro- (M + NH₄ ⁺) (2,2,3,3-tetrafluoro- acetic acid(compound 2.7) propoxy)-benzoyl]- and 5-Methanesulfonyl-2-piperazin-1-yl}- (2,2,3,3-tetrafluoro- benzonitrile propoxy)-benzoicacid (compound 2.22) 214 2,5-Difluoro-4-{4-[5-2,5-Difluoro-4-piperazin-1- 553.2 methanesulfonyl-2-yl-benzonitrile-trifluoro- (M + NH₄ ⁺) (2,2,3,3-tetrafluoro- acetic acid(compound 2.8) propoxy)-benzoyl]- and 5-Methanesulfonyl-2-piperazin-1-yl}- (2,2,3,3-tetrafluoro- benzonitrile propoxy)-benzoicacid (compound 2.22) 215 3,5-Difluoro-4-{4-[5-3,5-Difluoro-4-piperazin-1- 553.0 methanesulfonyl-2- yl-benzonitriletrifluoro- (M + NH₄ ⁺) (2,2,3,3-tetrafluoro- acetic acid (compound 2.13)propoxy)-benzoyl]- and 5-Methanesulfonyl-2- piperazin-1-yl}-(2,2,3,3-tetrafluoro- benzonitrile propoxy)-benzoic acid (compound 2.22)216 2,6-Difluoro-4-{4-[5- 2,6-Difluoro-4-piperazin-1- 553.2methanesulfonyl-2- yl-benzonitrile trifluoro- (M + NH₄ ⁺)(2,2,3,3-tetrafluoro- acetic acid (compound 2.14) propoxy)-benzoyl]- and5-Methanesulfonyl-2- piperazin-1-yl}- (2,2,3,3-tetrafluoro- benzonitrilepropoxy)-benzoic acid (compound 2.22) 217 [4-(2-Fluoro-4- 1-(2-Fluoro-4-588.3 methanesulfonyl- methanesulfonyl-phenyl)- (M + NH₄ ⁺)phenyl)-piperazin-1-yl]- piperazin (commercial) [5-methanesulfonyl-2-and 5-Methanesulfonyl-2- (2,2,3,3-tetrafluoro- (2,2,3,3-tetrafluoro-propoxy)-phenyl]- propoxy)-benzoic acid methanone (compound 2.22) 218[4-(2,6-Difluoro-4- 1-(2,6-Difluoro-4- 517.3 methanesulfonyl-methanesulfonyl-phenyl)- phenyl)-piperazin-1-yl]- piperazinetrifluoro-acetic (2-isopropoxy-5- acid (compound 2.23) andmethanesulfonyl- 2-Isopropoxy-5- phenyl)-methanonemethanesulfonyl-benzoic acid (compound 1.2) 219 3-Chloro-4-[4-(2-3-Chloro-4-piperazin-1-yl- 462.3 isopropoxy-5- benzonitrile (WO 9625414)methanesulfonyl- and 2-Isopropoxy-5- benzoyl)-piperazin-1-yl]-methanesulfonyl-benzoic benzonitrile acid (compound 1.2) 220[4-(2-Chloro-4-nitro- 1-(2-Chloro-4-nitro- 482.3phenyl)-piperazin-1-yl]- phenyl)-piperazine (EP (2-isopropoxy-5- 257864)and 2-Isopropoxy- methanesulfonyl- 5-methanesulfonyl-benzoicphenyl)-methanone acid (compound 1.2) 221 3-[4-(2-Isopropoxy-5-3-Piperazin-1-yl- 428.4 methanesulfonyl- benzonitrile (WO02068399)benzoyl)-piperazin-1-yl]- and 2-Isopropoxy-5- benzonitrilemethanesulfonyl-benzoic acid (compound 1.2) 222 [4-(3,5-Dichloro-1-(3,5-Dichloro-pyridin-4- 474.0 pyridin-4-yl)-piperazin- yl)-piperazine(commercial) 1-yl]-(2-isopropoxy-5- and 2-Isopropoxy-5- methanesulfonyl-methanesulfonyl-benzoic phenyl)-methanone acid (compound 1.2) 2235-Chloro-2-{4-[5- 5-Chloro-2-piperazin-1-yl- 502.1 methanesulfonyl-2-benzonitrile (WO9625414) (2,2,2-trifluoro-ethoxy)- and5-Methanesulfonyl-2- benzoyl]-piperazin-1-yl}- (2,2,2-trifluoro-ethoxy)-benzonitrile benzoic acid (compound 1.5) 224 [4-(4-Chloro-2-fluoro-1-(4-Chloro-2-fluoro- 495.4 phenyl)-piperazin-1-yl]- phenyl)-piperazine[5-methanesulfonyl-2- hydrochloride (commercial)(2,2,2-trifluoro-ethoxy)- and 5-Methanesulfonyl-2- phenyl]-methanone(2,2,2-trifluoro-ethoxy)- benzoic acid (compound 1.5) 225[4-(4-Chloro-3- 1-(4-Chloro-3- 545.3 trifluoromethyl-phenyl)-trifluoromethyl-phenyl)- piperazin-1-yl]-[5- piperazine (commercial)methanesulfonyl-2- and 5-Methanesulfonyl-2- (2,2,2-trifluoro-ethoxy)-(2,2,2-trifluoro-ethoxy)- phenyl]-methanone benzoic acid (compound 1.5)226 [4-(2,5-Difluoro-4- 1-(2,5-Difluoro-4- 574.3 methanesulfonyl-methanesulfonyl-phenyl)- (M + NH₄ ⁺) phenyl)-piperazin-1-yl]- piperazinetrifluoro-acetic [5-methanesulfonyl-2- acid (compound 2.20) and(2,2,2-trifluoro-ethoxy)- 5-Methanesulfonyl-2-(2,2,2- phenyl]-methanonetrifluoro-ethoxy)-benzoic acid (compound 1.5) 227 [4-(2,6-Difluoro-4-1-(2,6-Difluoro-4- 557.4 methanesulfonyl- methanesulfonyl-phenyl)-phenyl)-piperazin-1-yl]- piperazine trifluoro-acetic[5-methanesulfonyl-2- acid (compound 2.23) and (2,2,2-trifluoro-ethoxy)-5-Methanesulfonyl-2-(2,2,2- phenyl]-methanone trifluoro-ethoxy)-benzoicacid (compound 1.5) 228 5-Chloro-2-[4-(2- 5-Chloro-2-piperazin-1-yl-474.1 cyclopropylmethoxy-5- benzonitrile (WO9625414) methanesulfonyl-and 2-Cyclopropylmethoxy- benzoyl)-piperazin-1-yl]-5-methanesulfonyl-benzoic benzonitrile acid (compound 1.4) 229[4-(4-Chloro-2-fluoro- 1-(4-Chloro-2-fluoro- 467.3phenyl)-piperazin-1-yl]- phenyl)-piperazine (2-cyclopropylmethoxy-hydrochloride (commercial) 5-methanesulfonyl- and 2-Cyclopropylmethoxy-phenyl)-methanone 5-methanesulfonyl-benzoic acid (compound 1.4) 230(2-Cyclopropylmethoxy- 1-(3,4-Dichloro-phenyl)- 483.3 5-methanesulfonyl-piperazine (commercial) phenyl)-[4-(3,4- and 2-Cyclopropylmethoxy-dichloro-phenyl)- 5-methanesulfonyl-benzoic piperazin-1-yl]- acid(compound 1.4) methanone 231 [4-(4-Chloro-3- 1-(4-Chloro-3- 517.0trifluoromethyl-phenyl)- trifluoromethyl-phenyl)- piperazin-1-yl]-(2-piperazine (commercial) cyclopropylmethoxy-5- and 2-Cyclopropylmethoxy-methanesulfonyl- 5-methanesulfonyl-benzoic phenyl)-methanone acid(compound 1.4) 232 (2-Cyclopropylmethoxy- 1-(2,5-Difluoro-4- 546.35-methanesulfonyl- methanesulfonyl-phenyl)- (M + NH₄ ⁺)phenyl)-[4-(2,5-difluoro- piperazine trifluoro-acetic 4-methanesulfonyl-acid (compound 2.20) and phenyl)-piperazin-1-yl]-2-Cyclopropylmethoxy-5- methanone methanesulfonyl-benzoic acid (compound1.4) 233 (2-Cyclopropylmethoxy- 1-(2,6-Difluoro-4- 546.35-methanesulfonyl- methanesulfonyl-phenyl)- (M + NH₄ ⁺)phenyl)-[4-(2,6-difluoro- piperazine trifluoro-acetic 4-methanesulfonyl-acid (compound 2.23) and phenyl)-piperazin-1-yl]-2-Cyclopropylmethoxy-5- methanone methanesulfonyl-benzoic acid (compound1.4) 234 4-[4-(2-tert-Butoxy-5- 2,5-Difluoro-4-piperazin-1- 478.1methanesulfonyl- yl-benzonitrile-trifluoro- benzoyl)-piperazin-1-yl]-acetic acid (compound 2.8) 2,5-difluoro-benzonitrile and2-tert-Butoxy-5- methanesulfonyl-benzoic acid (compound 2.19) 2354-[4-(2-tert-Butoxy-5- 3,5-Difluoro-4-piperazin-1- 478.1methanesulfonyl- yl-benzonitrile trifluoro benzoyl)-piperazin-1-yl]-acetic acid (compound 2.13) 3,5-difluoro-benzonitrile and2-tert-Butoxy-5- methanesulfonyl-benzoic acid (compound 2.19) 2364-[4-(2-tert-Butoxy-5- 2,6-Difluoro-4-piperazin-1- 478.1methanesulfonyl- yl-benzonitrile trifluoro- benzoyl)-piperazin-1-yl]-acetic acid (compound 2.14) 2,6-difluoro-benzonitrile and2-tert-Butoxy-5- methanesulfonyl-benzoic acid (compound 2.19) 237(2-tert-Butoxy-5- 1-(2-Fluoro-4- 530.2 methanesulfonyl-methanesulfonyl-phenyl)- (M + NH₄ ⁺) phenyl)-[4-(2-fluoro-4- piperazine(commercial) methanesulfonyl- and 2-tert-Butoxy-5-phenyl)-piperazin-1-yl]- methanesulfonyl-benzoic methanone acid(compound 2.19) 238 2-[4-(2-tert-Butoxy-5- 2-Piperazin-1-yl-5- 527.3methanesulfonyl- trifluoromethyl-benzonitrile (M + NH₄ ⁺)benzoyl)-piperazin-1-yl]- (compound 5.2) and 2-tert- 5-trifluoromethyl-Butoxy-5-methanesulfonyl- benzonitrile benzoic acid (compound 2.19) 239(2-tert-Butoxy-5- 1-(2,3-Difluoro-4- 548.3 methanesulfonyl-methanesulfonyl-phenyl)- (M + NH₄ ⁺) phenyl)-[4-(2,3-difluoro-piperazine (compound 5.3) 4-methanesulfonyl- and 2-tert-Butoxy-5-phenyl)-piperazin-1-yl]- methanesulfonyl-benzoic methanone acid(compound 2.19) 240 (2-tert-Butoxy-5- 1-(3-Chloro-5- 520.3methanesulfonyl- trifluoromethyl-pyridin-2- phenyl)-[4-(3-chloro-5-yl)-piperazine (commercial) trifluoromethyl-pyridin- and2-tert-Butoxy-5- 2-yl)-piperazin-1-yl]- methanesulfonyl-benzoicmethanone acid (compound 2.19) 241 (2-tert-Butoxy-5-1-(5-Chloro-pyridin-2-yl)- 452.3 methanesulfonyl- piperazine(WO01062751) phenyl)-[4-(5-chloro- and 2-tert-Butoxy-5-pyridin-2-yl)-piperazin- methanesulfonyl-benzoic 1-yl]-methanone acid(compound 2.19) 242 (2-tert-Butoxy-5- 1-(5-Trifluoromethyl- 486.4methanesulfonyl- pyridin-2-yl)- phenyl)-[4-(5- piperazine (commercial)trifluoromethyl-pyridin- and 2-tert-Butoxy-5- 2-yl)-piperazin-1-yl]-methanesulfonyl-benzoic methanone acid (compound 2.19) 2434-[4-(2-tert-Butoxy-5- 2-Fluoro-4-piperazin-1-yl- 460.3 methanesulfonyl-benzonitrile (WO 9808835) benzoyl)-piperazin-1-yl]- and 2-tert-Butoxy-5-2-fluoro-benzonitrile methanesulfonyl-benzoic acid (compound 2.19) 2444-[4-(2-tert-Butoxy-5- 3-Fluoro-4-piperazin-1-yl- 460.3 methanesulfonyl-benzonitrile (WO9625414) benzoyl)-piperazin-1-yl] and 2-tert-Butoxy-5-3-fluoro-benzonitrile methanesulfonyl-benzoic acid (compound 2.19) 245(2-tert-Butoxy-5- 1-(4-Trifluoromethyl- 485.5 methanesulfonyl-phenyl)-piperazine phenyl)-[4-(4- (commercial) and 2-tert-trifluoromethyl-phenyl)- Butoxy-5-methanesulfonyl- piperazin-1-yl]-benzoic acid (compound 2.19) methanone 246 (2-tert-Butoxy-5-1-(3-Fluoro-4- 503.1 methanesulfonyl- trifluoromethyl-phenyl)-phenyl)-[4-(3-fluoro-4- piperazine (compound 5.1)trifluoromethyl-phenyl)- and 2-tert-Butoxy-5- piperazin-1-yl]-methanesulfonyl-benzoic methanone acid (compound 2.19) 247(2-tert-Butoxy-5- 1-(2-Fluoro-4- 503.3 methanesulfonyl-trifluoromethyl-phenyl)- phenyl)-[4-(2-fluoro-4- piperazine (compound1.1) trifluoromethyl-phenyl)- and 2-tert-Butoxy-5- piperazin-1-yl]-methanesulfonyl-benzoic methanone acid (compound 2.19) 2486-[4-(2-tert-Butoxy-5- 6-Piperazin-1-yl- 443.4 methanesulfonyl-nicotinonitrile benzoyl)-piperazin-1-yl]- (commercial) and 2-tert-nicotinonitrile Butoxy-5-methanesulfonyl- benzoic acid (compound 2.19)249 (2-tert-Butoxy-5- 1-(2,5-Difluoro-4- 548.3 methanesulfonyl-methanesulfonyl-phenyl)- (M + NH₄ ⁺) phenyl)-[4-(2,5-difluoro-piperazine trifluoro-acetic 4-methanesulfonyl- acid (compound 2.20) andphenyl)-piperazin-1-yl]- 2-tert-Butoxy-5- methanonemethanesulfonyl-benzoic acid (compound 2.19) 250 (2-tert-Butoxy-5-1-(2,6-Difluoro-4- 548.3 methanesulfonyl- methanesulfonyl-phenyl)- (M +NH₄ ⁺) phenyl)-[4-(2,6-difluoro- piperazine trifluoro-acetic4-methanesulfonyl- acid (compound 2.23) and phenyl)-piperazin-1-yl]-2-tert-Butoxy-5- methanone methanesulfonyl-benzoic acid (compound 2.19)251 [4-(3,4-Dichloro- 1-(3,4-Dichloro-phenyl)- 511.0phenyl)-piperazin-1-yl]- piperazine (commercial) [5-methanesulfonyl-2-and 5-Methanesulfonyl-2- (2,2,2-trifluoro-ethoxy)-(2,2,2-trifluoro-ethoxy)- phenyl]-methanone benzoic acid (compound 1.5)252 2-[4-(2-Isopropoxy-5- 2-Piperazin-1-yl- 429.5 methanesulfonyl-nicotinonitrile benzoyl)-piperazin-1-yl]- (commercial) and 2-nicotinonitrile Isopropoxy-5- methanesulfonyl-benzoic acid (compound1.2) 253 (2-Isopropoxy-5- 2-Piperazin-1-yl-4- 473.0 methanesulfonyl-trifluoromethyl- phenyl)-[4-(4- pyrimidine (commercial) trifluoromethyl-and 2-Isopropoxy-5- pyrimidin-2-yl)- methanesulfonyl-benzoicpiperazin-1-yl]- acid (compound 1.2) methanone 254rac-[4-(2,5-Difluoro-4- 1-(2,5-Difluoro-4- 571.0 methanesulfonyl-methanesulfonyl-phenyl)- phenyl)-piperazin-1-yl]- piperazinetrifluoro-acetic [5-methanesulfonyl-2- acid (compound 2.20) and(2,2,2-trifluoro-1- rac-5-Methanesulfonyl-2- methyl-ethoxy)-phenyl]-(2,2,2-trifluoro-1-methyl- methanone ethoxy)-benzoic acid (compound 3.1)255 rac-[4-(2,6-Difluoro-4- 1-(2,6-Difluoro-4- 571.2 methanesulfonyl-methanesulfonyl-phenyl)- phenyl)-piperazin-1-yl]- piperazinetrifluoro-acetic [5-methanesulfonyl-2- acid (compound 2.23) and(2,2,2-trifluoro-1- rac-5-Methanesulfonyl-2- methyl-ethoxy)-phenyl]-(2,2,2-trifluoro-1-methyl- methanone ethoxy)-benzoic acid (compound 3.1)256 rac-5-Chloro-2-{4-[5- 5-Chloro-2-piperazin-1-yl- 516.2methanesulfonyl-2- benzonitrile (WO9625414) (2,2,2-trifluoro-1- andrac-5-Methanesulfonyl- methyl-ethoxy)- 2-(2,2,2-trifluoro-1-methyl-benzoyl]-piperazin-1-yl}- ethoxy)-benzoic acid benzonitrile (compound3.1) 257 rac-[4-(4-Chloro-2- 1-(4-Chloro-2-fluoro- 509.3 fluoro-phenyl)-phenyl)-piperazine piperazin-1-yl]-[5- hydrochloride (commercial)methanesulfonyl-2- and rac-5-Methanesulfonyl- (2,2,2-trifluoro-1-2-(2,2,2-trifluoro-1-methyl- methyl-ethoxy)-phenyl]- ethoxy)-benzoicacid methanone (compound 3.1) 258 rac-[4-(3,4-Dichloro-1-(3,4-Dichloro-phenyl)- 525.2 phenyl)-piperazin-1-yl]- piperazine(commercial) [5-methanesulfonyl-2- and rac-5-Methanesulfonyl-(2,2,2-trifluoro-1- 2-(2,2,2-trifluoro-1-methyl- methyl-ethoxy)-phenyl]-ethoxy)-benzoic acid methanone (compound 3.1) 259 rac-[4-(4-Chloro-3-1-(4-Chloro-3- 559.0 trifluoromethyl-phenyl)- trifluoromethyl-phenyl)-piperazin-1-yl]-[5- piperazine (commercial) methanesulfonyl-2- andrac-5-Methanesulfonyl- (2,2,2-trifluoro-1- 2-(2,2,2-trifluoro-1-methyl-methyl-ethoxy)-phenyl]- ethoxy)-benzoic acid methanone (compound 3.1)260 rac-3,5-Difluoro-4-{4-[5- 3,5-Difluoro-4-piperazin-1- 518.2methanesulfonyl-2- yl-benzonitrile trifluoro- (2,2,2-trifluoro-1- aceticacid (compound 2.13) methyl-ethoxy)- and rac-5-Methanesulfonyl-benzoyl]-piperazin-1-yl}- 2-(2,2,2-trifluoro-1-methyl- benzonitrileethoxy)-benzoic acid (compound 3.1) 261 rac-2,5-Difluoro-4-{4-[5-2,5-Difluoro-4-piperazin-1- 518.0 methanesulfonyl-2-yl-benzonitrile-trifluoro- (2,2,2-trifluoro-1- acetic acid (compound2.8) methyl-ethoxy)- and rac-5-Methanesulfonyl-benzoyl]-piperazin-1-yl-}- 2-(2,2,2-trifluoro-1-methyl- benzonitrileethoxy)-benzoic acid (compound 3.1) 262 rac-2,6-Difluoro-4-{4-[5-2,6-Difluoro-4-piperazin-1- 517.8 methanesulfonyl-2- yl-benzonitriletrifluoro- (2,2,2-trifluoro-1- acetic acid (compound 2.14)methyl-ethoxy)- and rac-5-Methanesulfonyl- benzoyl]-piperazin-1-yl}-2-(2,2,2-trifluoro-1-methyl- benzonitrile ethoxy)-benzoic acid (compound3.1) 263 (2-Cyclopropylmethoxy- 2-Piperazin-1-yl-4- 485.15-methanesulfonyl- trifluoromethyl-pyrimidine phenyl)-[4-(4-(commercial) and 2- trifluoromethyl- Cyclopropylmethoxy-5-pyrimidin-2-yl)- methanesulfonyl-benzoic piperazin-1-yl]- acid (compound1.4) methanone 264 (2-Isopropoxy-5- 4-Piperazin-1-yl-2- 473.1methanesulfonyl- trifluoromethyl-pyrimidine phenyl)-[4-(2-trifluoro-acetic acid trifluoromethyl- (WO030249) and 2-pyrimidin-4-yl)- Isopropoxy-5- piperazin-1-yl]- methanesulfonyl-benzoicmethanone acid (compound 1.2) 265 (2-tert-Butoxy-5- 1-(3-Fluoro-5- 504.0methanesulfonyl- trifluoromethyl-pyridin-2- phenyl)-[4-(3-fluoro-5-yl)-piperazine (compound trifluoromethyl-pyridin- 5.5) and2-tert-Butoxy-5- 2-yl)-piperazin-1-yl]- methanesulfonyl-benzoicmethanone acid (compound 2.19) 266 (2-tert-Butoxy-5- 2-Piperazin-1-yl-4-487.1 methanesulfonyl- trifluoromethyl- phenyl)-[4-(4- pyrimidine(commercial) trifluoromethyl- and 2-tert-Butoxy-5- pyrimidin-2-yl)-methanesulfonyl-benzoic piperazin-1-yl]- acid (compound 2.19) methanone267 [5-Methanesulfonyl-2- 2-Piperazin-1-yl-4- 513.3(2,2,2-trifluoro-ethoxy)- trifluoromethyl- phenyl]-[4-(4- pyrimidine(commercial) trifluoromethyl- and 5-Methanesulfonyl-2- pyrimidin-2-yl)-(2,2,2-trifluoro-ethoxy)- piperazin-1-yl]- benzoic acid (compound 1.5)methanone 268 rac-[5-Methanesulfonyl- 2-Piperazin-1-yl-4- 527.02-(2,2,2-trifluoro-1- trifluoromethyl- methyl-ethoxy)-phenyl]-pyrimidine (commercial) [4-(4-trifluoromethyl- andrac-5-Methanesulfonyl- pyrimidin-2-yl)- 2-(2,2,2-trifluoro-1-methyl-piperazin-1-yl]- ethoxy)-benzoic acid methanone (compound 3.1) 269[4-(2,5-Difluoro-4- 1-(2,5-Difluoro-4- 571.0 methanesulfonyl-methanesulfonyl-phenyl)- phenyl)-piperazin-1-yl]- piperazinetrifluoro-acetic [5-methanesulfonyl-2- acid and 5-((S)-2,2,2-trifluoro-1- Methanesulfonyl-2-((S)- methyl-ethoxy)-phenyl]-2,2,2-trifluoro-1-methyl- methanone ethoxy)-benzoic acid (compound 5.6)270 [4-(2,5-Difluoro-4- 1-(2,5-Difluoro-4- 571.0 methanesulfonyl-methanesulfonyl-phenyl)- phenyl)-piperazin-1-yl]- piperazinetrifluoro-acetic [5-methanesulfonyl-2- acid (compound 2.20) and((R)-2,2,2-trifluoro-1- 5-Methanesulfonyl-2-((R)-methyl-ethoxy)-phenyl]- 2,2,2-trifluoro-1-methyl- methanoneethoxy)-benzoic acid (compound 5.7) 271 [4-(2,6-Difluoro-4-1-(2,6-Difluoro-4- 571.2 methanesulfonyl- methanesulfonyl-phenyl)-phenyl)-piperazin-1-yl]- piperazine trifluoro-acetic[5-methanesulfonyl-2- acid (compound 2.23) and ((S)-2,2,2-trifluoro-1-5-Methanesulfonyl-2-((S)- methyl-ethoxy)-phenyl]-2,2,2-trifluoro-1-methyl- methanone ethoxy)-benzoic acid (compound 5.6)272 [4-(2,6-Difluoro-4- 1-(2,6-Difluoro-4- 571.2 methanesulfonyl-methanesulfonyl-phenyl)- phenyl)-piperazin-1-yl]- piperazinetrifluoro-acetic [5-methanesulfonyl-2- acid (compound 2.23) and((R)-2,2,2-trifluoro-1- 5-Methanesulfonyl-2-((R)-methyl-ethoxy)-phenyl]- 2,2,2-trifluoro-1-methyl- methanoneethoxy)-benzoic acid (compound 5.7) 273 rac-[5-Methanesulfonyl-4-Piperazin-1-yl-2- 527.0 2-(2,2,2-trifluoro-1-trifluoromethyl-pyrimidine methyl-ethoxy)-phenyl]- trifluoro-acetic acid[4-(2-trifluoromethyl- (WO030249) and rac-5- pyrimidin-4-yl)-Methanesulfonyl-2-(2,2,2- piperazin-1-yl]- trifluoro-1-methyl-ethoxy)-methanone benzoic acid (compound 3.1) 274 rac-[5-Methanesulfonyl-4-Piperazin-1-yl-6- 527.2 2-(2,2,2-trifluoro-1-trifluoromethyl-pyrimidine methyl-ethoxy)-phenyl]- trifluoro-acetic acid[4-(6-trifluoromethyl- (compound 2.24) and rac-5- pyrimidin-4-yl)-Methanesulfonyl-2-(2,2,2- piperazin-1-yl]- trifluoro-1-methyl-ethoxy)-methanone benzoic acid (compound 3.1) 275 rac-[5-Methanesulfonyl-2-Piperazin-1-yl-5- 527.2 2-(2,2,2-trifluoro-1-trifluoromethyl-pyrimidine methyl-ethoxy)-phenyl]- (compound 2.25) andrac-5- [4-(5-trifluoromethyl- Methanesulfonyl-2-(2,2,2- pyrimidin-2-yl)-trifluoro-1-methyl-ethoxy)- piperazin-1-yl]- benzoic acid (compound 3.1)methanone 276 (2-Isopropoxy-5- 2-Piperazin-1-yl-5- 473.1methanesulfonyl- trifluoromethyl-pyrimidine phenyl)-[4-(5- (compound2.25) and 2- trifluoromethyl- Isopropoxy-5- pyrimidin-2-yl)-methanesulfonyl-benzoic piperazin-1-yl]- acid (compound 1.2) methanone277 (2-Cyclopropylmethoxy- 4-Piperazin-1-yl-2- 485.1 5-methanesulfonyl-trifluoromethyl-pyrimidine phenyl)-[4-(2- trifluoro-acetic acidtrifluoromethyl- (WO030249) and 2- pyrimidin-4-yl)-Cyclopropylmethoxy-5- piperazin-1-yl]- methanesulfonyl-benzoic methanoneacid (compound 1.4) 278 (2-Cyclopropylmethoxy- 4-Piperazin-1-yl-6- 485.55-methanesulfonyl- trifluoromethyl-pyrimidine phenyl)-[4-(6-trifluoro-acetic acid trifluoromethyl- (compound 2.24) and 2-pyrimidin-4-yl)- Cyclopropylmethoxy-5- piperazin-1-yl]-methanesulfonyl-benzoic methanone acid (compound 1.4) 279[5-Methanesulfonyl-2- 4-Piperazin-1-yl-2- 513.3(2,2,2-trifluoro-ethoxy)- trifluoromethyl-pyrimidine phenyl]-[4-(2-trifluoro-acetic acid trifluoromethyl- (WO030249) and 5-pyrimidin-4-yl)- Methanesulfonyl-2-(2,2,2- piperazin-1-yl]-trifluoro-ethoxy)-benzoic methanone acid (compound 1.5) 280[5-Methanesulfonyl-2- 4-Piperazin-1-yl-6- 513.3(2,2,2-trifluoro-ethoxy)- trifluoromethyl-pyrimidine phenyl]-[4-(6-trifluoro-acetic acid trifluoromethyl- (compound 2.24) and 5-pyrimidin-4-yl)- Methanesulfonyl-2-(2,2,2- piperazin-1-yl]-trifluoro-ethoxy)-benzoic methanone acid (compound 1.5)

In analogy to Example 1.2 (b) compounds 3.1 to 3.5 of the followingtable were prepared from 2-chloro-5-methanesulfonyl-benzoic acid and theappropriate alcohol:

Expl. No Compound Name Alcohol MS (m/e) 3.1 rac-5-Methanesulfonyl-rac-1,1,1-Trifluoro- 311.3 (MH−) 2-(2,2,2-trifluoro-1- propan-2-olmethyl ethoxy)-benzoic acid (compound 3.1) 3.2 2-Cyclohexyloxy-5-Cyclohexanol 297.3 (MH−) methanesulfonyl-benzoic acid (compound 3.2) 3.32-(2,2-Dimethyl- 2,2-Dimethyl- 285.1 (MH−) propoxy)-5- propan-1-olmethanesulfonyl-benzoic acid (compound 3.3) 3.4 2-Cyclobutoxy-5-cyclobutanol 269.3 (MH−) methanesulfonyl-benzoic acid (compound 3.4) 3.5rac-2-sec-Butoxy-5- Butan-2-ol 271.4 (MH−) methanesulfonyl-benzoic acid(compound 3.5)

In analogy to Example 5 compounds 281 to 326 of the following table wereprepared from the acid derivatives and piperazine derivatives.

Expl. MW found No. Systematic Name Starting materials (MH⁺) 2811-{4-[4-(2- 1-(3-Fluoro-4-piperazin-1- 503.5 Cyclohexyloxy-5-yl-phenyl)-ethanone methanesulfonyl- (WO9714690) and 2-benzoyl)-piperazin-1-yl]- Cyclohexyloxy-5- 3-fluoro-phenyl}-methanesulfonyl-benzoic ethanone acid (compound 3.2) 2824-[4-(2-Cyclohexyloxy- 4-Piperazin-1-yl- 468.5 5-methanesulfonyl-benzonitrile (commercial) benzoyl)-piperazin-1-yl]- and2-Cyclohexyloxy-5- benzonitrile methanesulfonyl-benzoic acid (compound3.2) 283 4-[4-(2-Cyclohexyloxy- 3-Fluoro-4-piperazin-1-yl- 486.55-methanesulfonyl- benzonitrile (WO9625414) benzoyl)-piperazin-1-yl]-and 2-Cyclohexyloxy-5- 3-fluoro-benzonitrile methanesulfonyl-benzoicacid (compound 3.2) 284 4-[4-(2-Cyclohexyloxy-2-Fluoro-4-piperazin-1-yl- 486.5 5methanesulfonyl- benzonitrile (WO9808835) benzoyl)-piperazin-1-yl]- and 2-Cyclohexyloxy-5-2-fluoro-benzonitrile methanesulfonyl-benzoic acid (compound 3.2) 285(2-Cyclohexyloxy-5- 1-(4-Trifluoromethyl- 511.5 methanesulfonyl-phenyl)-piperazine phenyl)-[4-(4- (commercial) and 2-trifluoromethyl-phenyl)- Cyclohexyloxy-5- piperazin-1-yl]-methanesulfonyl-benzoic methanone acid (compound 3.2) 286(2-Cyclohexyloxy-5- 1-(2-Fluoro-4- 529.5 methanesulfonyl-trifluoromethyl-phenyl)- phenyl)-[4-(2-fluoro-4- piperazine (compoundtrifluoromethyl-phenyl)- 1.1) and 2-Cyclohexyloxy-5- piperazin-1-yl]-methanesulfonyl-benzoic methanone acid (compound 3.2) 287(2-Cyclohexyloxy-5- 1-(3-Fluoro-4- 529.3 methanesulfonyl-trifluoromethyl-phenyl)- phenyl)-[4-(3-fluoro-4- piperazine (compound5.1) trifluoromethyl-phenyl)- and 2-Cyclohexyloxy-5- piperazin-1-yl]-methanesulfonyl-benzoic methanone acid (compound 3.2) 288(2-Cyclohexyloxy-5- 1-(2-Fluoro-4- 539.5 methanesulfonyl-methanesulfonyl-phenyl)- phenyl)-[4-(2-fluoro-4- piperazine (commercial)methanesulfonyl- and 2-Cyclohexyloxy-5- phenyl)-piperazin-1-yl]-methanesulfonyl-benzoic methanone acid (compound 3.2) 2891-(4-{4-[2-(2,2- 1-(3-Fluoro-4-piperazin-1- 491.5 Dimethyl-propoxy)-5-yl-phenyl)-ethanone methanesulfonyl- (WO9714690) and 2-(2,2-benzoyl]-piperazin- Dimethyl-propoxy)-5- 1-yl}-3-fluoro-phenyl)-methanesulfonyl-benzoic methanone acid (compound 3.3) 2904-{4-[2-(2,2-Dimethyl- 4-Piperazin-1-yl- 456.6propoxy)-5-methanesulfonyl- benzonitrile (commercial)benzoyl]-piperazin-1- and 2-(2,2-Dimethyl- yl}-benzonitrile propoxy)-5-methanesulfonyl-benzoic acid (compound 3.3) 291 4-{4-[2-(2,2-Dimethyl-3-Fluoro-4-piperazin-1-yl- 474.4 propoxy)-5- benzonitrile (WO9625414)methanesulfonyl- and 2-(2,2-Dimethyl- benzoyl]-piperazin-1-yl}-propoxy)-5- 3-fluoro-benzonitrile methanesulfonyl-benzoic acid (compound3.3) 292 4-{4-[2-(2,2-Dimethyl- 2-Fluoro-4-piperazin-1-yl- 474.5propoxy)-5-methanesulfonyl- benzonitrile (WO 9808835)benzoyl]-piperazin-1- and 2-(2,2-Dimethyl- yl}-2-fluoro-benzonitrilepropoxy)-5- methanesulfonyl-benzoic acid (compound 3.3) 293[2-(2,2-Dimethyl- 1-(4-Trifluoromethyl- 499.4 propoxy)-5-phenyl)-piperazine methanesulfonyl- (commercial) and 2-(2,2-phenyl]-[4-(4- Dimethyl-propoxy)-5- trifluoromethyl-phenyl)-methanesulfonyl-benzoic piperazin-1-yl]- acid (compound 3.3) methanone294 [2-(2,2-Dimethyl- 1-(2-Fluoro-4- 517.5 propoxy)-5-methanesulfonyl-trifluoromethyl-phenyl)- phenyl]-[4-(2- piperazine (compoundfluoro-4-trifluoromethyl- 1.1) and 2-(2,2-Dimethyl-phenyl)-piperazin-1-yl]- propoxy)-5- methanone methanesulfonyl-benzoicacid (compound 3.3) 295 [2-(2,2-Dimethyl- 1-(3-Fluoro-4- 517.5propoxy)-5-methane trifluoromethyl-phenyl)- sulfonyl-phenyl]-[4-(3-piperazine (compound 5.1) fluoro-4-trifluoromethyl- and 2-(2,2-Dimethyl-phenyl)-piperazin-1-yl]- propoxy)-5- methanone methanesulfonyl-benzoicacid (compound 3.3) 296 [2-(2,2-Dimethyl- 1-(2-Fluoro-4- 527.3propoxy)-5- methanesulfonyl-phenyl)- methanesulfonyl- piperazine(commercial) phenyl]-[4-(2-fluoro-4- and 2-(2,2-Dimethyl-methanesulfonyl- propoxy)-5- phenyl)-piperazin-1-yl]-methanesulfonyl-benzoic methanone acid (compound 3.3) 297rac-1-(3-Fluoro-4-{4-[5- 1-(3-Fluoro-4-piperazin-1- 517.5methanesulfonyl-2- yl-phenyl)-ethanone (2,2,2-trifluoro-1-(WO9714690)and rac-5- methyl-ethoxy)- Methanesulfonyl-2-(2,2,2-benzoyl]-piperazin-1-yl}- trifluoro-1-methyl-ethoxy)- phenyl)-ethanonebenzoic acid (compound 3.1) 298 rac-4-{4-[5- 4-Piperazin-1-yl- 482.5Methanesulfonyl-2- benzonitrile (commercial) (2,2,2-trifluoro-1- andrac-5-Methanesulfonyl- methyl-ethoxy)- 2-(2,2,2-trifluoro-1-methyl-benzoyl]-piperazin-1-yl}- ethoxy)-benzoic acid benzonitrile (compound3.1) 299 rac-3-Fluoro-4-{4-[5- 3-Fluoro-4-piperazin-1-yl- 500.4methanesulfonyl-2- benzonitrile (WO9625414) (2,2,2-trifluoro-1- andrac-5-Methanesulfonyl- methyl-ethoxy)- 2-(2,2,2-trifluoro-1-methyl-benzoyl]-piperazin-1-yl}- ethoxy)-benzoic acid benzonitrile (compound3.1) 300 rac-2-Fluoro-4-{4-[5- 2-Fluoro-4-piperazin-1-yl 500.4methanesulfonyl-2- benzonitrile (WO 9808835) (2,2,2-trifluoro-1- andrac-5-Methanesulfonyl- methyl-ethoxy)- 2-(2,2,2-trifluoro-1-methyl-benzoyl]-piperazin-1-yl}- ethoxy)-benzoic acid benzonitrile (compound3.1) 301 rac-5-Methanesulfonyl- 1-(4-Trifluoromethyl- 525.32-(2,2,2-trifluoro-1- phenyl)-piperazine methyl-ethoxy)-phenyl]-(commercial) and rac-5- [4-(4-trifluoromethyl- Methanesulfonyl-2-(2,2,2-phenyl)-piperazin-1-yl]- trifluoro-1-methyl-ethoxy)- methanone benzoicacid (compound 3.1) 302 rac-[4-(2-Fluoro-4- 1-(2-Fluoro-4- 543.5trifluoromethyl-phenyl)- trifluoromethyl-phenyl)- piperazin-1-yl]-[5-piperazine (compound methanesulfonyl-2- 1.1) and rac-5-Methanesulfonyl-(2,2,2-trifluoro-1- 2-(2,2,2-trifluoro- methyl-ethoxy)-phenyl]-1-methyl-ethoxy)-benzoic methanone acid (compound 3.1) 303rac-[4-(3-Fluoro-4- 1-(3-Fluoro-4- 543.5 trifluoromethyl-phenyl)-trifluoromethyl-phenyl)- piperazin-1-yl]-[5- piperazine (compound 5.1)methanesulfonyl-2- and rac-5-Methanesulfonyl- (2,2,2-trifluoro-1-2-(2,2,2-trifluoro-1-methyl- methyl-ethoxy)-phenyl]- ethoxy)-benzoicacid methanone (compound 3.1) 304 rac-[4-(2-Fluoro-4- 1-(2-Fluoro-4-553.0 methanesulfonyl- methanesulfonyl-phenyl)- phenyl)-piperazin-1-yl]-piperazine (commercial) [5-methanesulfonyl-2- and rac-5-Methanesulfonyl-(2,2,2-trifluoro-1- 2-(2,2,2-trifluoro-1-methyl- methyl-ethoxy)-phenyl]-ethoxy)-benzoic acid methanone (compound 3.1) 3054-{4-[5-Methanesulfonyl- 4-Piperazin-1-yl- 444.3 2-(2-methoxy-ethoxy)-benzonitrile (commercial) benzoyl]-piperazin-1-yl}- and5-Methanesulfonyl-2- benzonitrile (2-methoxy-ethoxy)- benzoic acid(compound 1.10) 306 3-Fluoro-4-{4-[5- 3-Fluoro-4-piperazin-1-yl- 462.5methanesulfonyl-2- benzonitrile (WO9625414) (2-methoxy-ethoxy)- and5-Methanesulfonyl-2- benzoyl]-piperazin-1-yl}- (2-methoxy-ethoxy)-benzonitrile benzoic acid (compound 1.10) 307 2-Fluoro-4-{4-[5-2-Fluoro-4-piperazin-1-yl- 462.5 methanesulfonyl-2- benzonitrile (WO9808835) (2-methoxy-ethoxy)- and 5-Methanesulfonyl-2-benzoyl]-piperazin-1-yl}- (2-methoxy-ethoxy)- benzonitrile benzoic acid(compound 1.10) 308 [4-(2-Fluoro-4- 1-(2-Fluoro-4- 505.5trifluoromethyl-phenyl)- trifluoromethyl-phenyl)- piperazin-1-yl]-[5-piperazine (compound 1.1) methanesulfonyl-2-(2- and5-Methanesulfonyl-2-(2- methoxy-ethoxy)- methoxy-ethoxy)-benzoicphenyl]-methanone acid (compound 1.10) 309 [4-(3-Fluoro-4-1-(3-Fluoro-4- 505.5 trifluoromethyl-phenyl)- trifluoromethyl-phenyl)-piperazin-1-yl]-[5- piperazine (compound 5.1) methanesulfonyl-2-(2- and5-Methanesulfonyl-2- methoxy-ethoxy)- (2-methoxy-ethoxy)-phenyl]-methanone benzoic acid (compound 1.10) 310 [4-(2-Fluoro-4-1-(2-Fluoro-4- 515.5 methanesulfonyl- methanesulfonyl-phenyl)-phenyl)-piperazin-1-yl]- piperazine (commercial) [5-methanesulfonyl-2-and 5-Methanesulfonyl-2- (2-methoxy-ethoxy)- (2-methoxy-ethoxy)-phenyl]-methanone benzoic acid (compound 1.10) 3111-{4-[4-(2-Cyclobutoxy- 1-(3-Fluoro-4-piperazin-1- 475.45-methanesulfonyl- yl-phenyl)-ethanone benzoyl)-piperazin-1-yl]-(WO9714690) and 2- 3-fluoro-phenyl}- Cyclobutoxy-5- ethanonemethanesulfonyl-benzoic acid (compound 3.4) 312 4-[4-(2-Cyclobutoxy-5-4-Piperazin-1-yl- 440.5 methanesulfonyl- benzonitrile (commercial)benzoyl)-piperazin-1-yl]- and 2-Cyclobutoxy-5- benzonitrilemethanesulfonyl-benzoic acid (compound 3.4) 313 4-[4-(2-Cyclobutoxy-5-3-Fluoro-4-piperazin-1-yl- 458.5 methanesulfonyl- benzonitrile(WO9625414) benzoyl)-piperazin-1-yl]- and 2-Cyclobutoxy-5-3-fluoro-benzonitrile methanesulfonyl-benzoic acid (compound 3.4) 3144-[4-(2-Cyclobutoxy-5- 2-Fluoro-4-piperazin-1-yl- 458.5 methanesulfonyl-benzonitrile (WO 9808835) benzoyl)-piperazin-1-yl]- and 2-Cyclobutoxy-5-2-fluoro-benzonitrile methanesulfonyl-benzoic acid (compound 3.4) 315(2-Cyclobutoxy-5- 1-(4-Trifluoromethyl- 483.5 methanesulfonyl-phenyl)-piperazine phenyl)-[4-(4- (commercial) and 2-trifluoromethyl-phenyl)- Cyclobutoxy-5- piperazin-1-yl]-methanesulfonyl-benzoic methanone acid (compound 3.4) 316(2-Cyclobutoxy-5- 1-(2-Fluoro-4- 501.5 methanesulfonyl-trifluoromethyl-phenyl)- phenyl)-[4-(2-fluoro-4- piperazine (compoundtrifluoromethyl-phenyl)- 1.1) and 2-Cyclobutoxy-5- piperazin-1-yl]-methanesulfonyl-benzoic methanone acid (compound 3.4) 317(2-Cyclobutoxy-5- 1-(3-Fluoro-4- 501.5 methanesulfonyl-trifluoromethyl-phenyl)- phenyl)-[4-(3-fluoro-4- piperazine (compound5.1) trifluoromethyl-phenyl)- and 2-Cyclobutoxy-5- piperazin-1-yl]-methanesulfonyl-benzoic methanone acid (compound 3.4) 318(2-Cyclobutoxy-5- 1-(2-Fluoro-4- 511.5 methanesulfonyl-methanesulfonyl-phenyl)- phenyl)-[4-(2-fluoro-4- piperazine (commercial)methanesulfonyl- and 2-Cyclobutoxy-5- phenyl)-piperazin-1-yl]-methanesulfonyl-benzoic methanone acid (compound 3.4) 319rac-1-{4-[4-(2-sec- 1-(3-Fluoro-4-piperazin-1- 477.4 Butoxy-5-yl-phenyl)-ethanone methanesulfonyl- (WO9714690) and rac-2-benzoyl)-piperazin-1-yl]- sec-Butoxy-5- 3-fluoro-phenyl}-methanesulfonyl-benzoic ethanone acid (compound 3.5) 320rac-4-[4-(2-sec-Butoxy- 4-Piperazin-1-yl- 442.5 5-methanesulfonyl-benzonitrile (commercial) benzoyl)-piperazin-1-yl]- andrac-2-sec-Butoxy-5- benzonitrile methanesulfonyl-benzoic acid (compound3.5) 321 rac-4-[4-(2-sec-Butoxy- 3-Fluoro-4-piperazin-1-yl- 460.55-methanesulfonyl- benzonitrile (WO9625414) benzoyl)-piperazin-1-yl]-and rac-2-sec-Butoxy-5- 3-fluoro-benzonitrile methanesulfonyl-benzoicacid (compound 3.5) 322 rac-4-[4-(2-sec-Butoxy-2-Fluoro-4-piperazin-1-yl- 460.5 5-methanesulfonyl- benzonitrile (WO9808835) benzoyl)-piperazin-1-yl]- and rac-2-sec-Butoxy-5-2-fluoro-benzonitrile methanesulfonyl-benzoic acid (compound 3.5) 323rac-(2-sec-Butoxy-5- 1-(4-Trifluoromethyl- 485.5 methanesulfonyl-phenyl)-piperazine phenyl)-[4-(4- (commercial) and rac-2-sec-trifluoromethyl-phenyl)- Butoxy-5-methanesulfonyl- piperazin-1-yl]-benzoic acid (compound 3.5) methanone 324 rac-(2-sec-Butoxy-5-1-(2-Fluoro-4- 503.3 methanesulfonyl- trifluoromethyl-phenyl)-phenyl)-[4-(2-fluoro-4- piperazine (compound trifluoromethyl- 1.1) andrac-2-sec-Butoxy- phenyl)-piperazin-1-yl]- 5-methanesulfonyl-benzoicmethanone acid (compound 3.5) 325 rac-(2-sec-Butoxy-5- 1-(3-Fluoro-4-503.3 methanesulfonyl- trifluoromethyl-phenyl)- phenyl)-[4-(3-fluoro-4-piperazine (compound 5.1) trifluoromethyl- and rac-2-sec-Butoxy-5-phenyl)-piperazin-1-yl]- methanesulfonyl-benzoic methanone acid(compound 3.5) 326 rac-(2-sec-Butoxy-5- 1-(2-Fluoro-4- 513.5methanesulfonyl- methanesulfonyl-phenyl)- phenyl)-[4-(2-fluoro-4-piperazine (commercial) methanesulfonyl- and rac-2-sec-Butoxy-5-phenyl)-piperazin-1-yl]- methanesulfonyl-benzoic methanone acid(compound 3.5)

EXAMPLE 4.1 Preparation of 6-Ethoxy-2-fluoro-3-methanesulfonyl-benzoicacid

(a) 3-Chlorosulfonyl-2,6-difluoro-benzoic acid

95 mmol of 2,6-difluorobenzoic acid in 19 ml of chorosulfonic acid wasstirred for 2 h at 150°. The mixture was poured into 200 ml of ice andstirred for 20 min. The resulting slurry was filtered, washed with waterand dried (20° overnight in the dessicator) to yield the title compoundas a colorless solid. MS (m/e): 279.4 (MNa⁺, 81%)

(b) 2,6-Difluoro-3-sulfino-benzoic acid

41 mmol of 3-chlorosulfonyl-2,6-difluoro-benzoic acid was slowly addedover 20 min. to a solution of 310 mmol sodium sulfite in 200 ml ofwater. The resulting mixture was stirred for one hour at roomtemperature, cooled to 0° C. and acidified with 20% aqueous sulfuricacid. The sulfinic acid was extracted with ethyl acetate, dried overMgSO₄ and concentrated to yield the title compound as a colorless solid.MS (m/e): 220.9 (M−H, 100%)

(c) 6-Ethoxy-2-fluoro-3-methanesulfonyl-benzoic acid

A mixture of 27 mmol 2,6-difluoro-3-sulfino-benzoic acid and 9 mmolNa₂CO₃ in 110 ml methanol was treated with 72 mmol of methyl iodide. Theresulting mixture was stirred overnight at 60°, concentrated and thedark residue dissolved in 100 ml of ethanol. 100 ml of 2 molar aqueousNaOH was added, and the mixture was refluxed for 2 hours. Concentrationto about 100 ml precipitated a yellowish solid which was filtered andtriturated with diethyl ether to give the crude title compound, whichwas used without further purification.

EXAMPLE 4.2 Preparation of1-(4-Trifluoromethanesulfonyl-phenyl)-piperazine

A mixture of 1 mmol 1-Bromo-4-trifluoromethanesulfonyl-benzene [Nodiffet al., J. Org. Chem. 25, 60 (1960)], 3 mmol of piperazine and 2 mmol ofpotassium carbonate in 5 ml of acetonitrile was refluxed for 2 hours.The resulting mixture was poured into water, extracted with ethylacetate, dried, concentrated and purified by column chromatography(SiO₂; Et2O/cyclohexane) to yield the title compound as a colorlesssolid. MS (m/e): 295.2 (MH⁺, 100%)

EXAMPLE 4.3 Preparation of 1-(2,4-Bis-trifluoromethyl-phenyl)-piperazinehydrochloride

(a) 4-(2,4-Bis-trifluoromethyl-phenyl)-piperazine-1-carboxylic acidtert-butyl ester

A mixture of 5 mmol 2,4-bis(trifluoromethyl)bromobenzene, 6 mmolN-BOC-piperazine, 8 mmol NaOtBu, 0.5 mmolrac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and 1 mmoltris-(dibenzylideneacetone)dipalladium chloroform complex in 20 mltoluene was stirred at 80° C. for 3 hours. The mixture was then dilutedwith water, extracted with ethyl acetate, dried and purified by columnchromatography (SiO₂; cyclohexane/ethyl acetate 9:1) to yield the titlecompound as a yellowish oil.

MS (m/e): 399.1 (MH⁺, 100%)

(b) 1-(2,4-Bis-trifluoromethyl-phenyl)-piperazine hydrochloride

3 mmol of 4-(2,4-Bis-trifluoromethyl-phenyl)-piperazine-1-carboxylicacid tert-butyl ester was stirred in 10 ml of 1,4-dioxane saturated withgaseous HCl. After 4 h at room temperature, the reaction mixture wasevaporated to dryness to yield the title compound as a colorless solid.MS (m/e): 299.3 (MH⁺, 100%)

EXAMPLE 4.4 Preparation of1-[4-(5-Methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-piperazine hydrochloride

(a)4-[4-(5-Methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-piperazine-1-carboxylicacid tert-butyl ester

A well stirred mixture of 0.015 mmol ofbis(tri-t-butylphosphine)palladium, 0.01 mmol of cetyltrimethylammoniumbromide, 2 mmol of powdered potassium hydroxide, 2 mmol of3-(4-bromo-phenyl)-5-methyl-[1,2,4]oxadiazole and 2.1 mmol ofN-BOC-piperazine in 1 ml of toluene was heated under Ar to 90° C. for 17hours. The resulting reaction mixture was diluted with water, extractedwith ethyl acetate and the product purified by column chromatography(SiO₂; cyclohexane/ethyl acetate 7:3) to yield the title compound as ayellowish solid. MS (m/e): 345.3 (MH⁺, 100%)

(b) 1-[4-(5-Methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-piperazinehydrochloride

1 mmol of4-[4-(5-Methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-piperazine-1-carboxylicacid tert-butyl ester was stirred in 3 ml of 1,4-dioxane saturated withgaseous HCl. After 2 h at room temperature, the reaction mixture wasevaporated to dryness to yield the tide compound as a colorless solid.MS (m/e): 245.1 (MH⁺, 100%)

EXAMPLE 4.5 Preparation of 1-(4-Oxazol-2-yl-phenyl)-piperazinehydrochloride

(a) 4-Bromo-N-(2,2-dimethoxy-ethyl)-benzamide

A solution of 24 mmol aminoacetaldehyde dimethylacetal was dissolved in30 ml of water and treated with 25 mmol of potassium hydrogencarbonate.A solution of 23 mmol of 4-bromobenzoyl chloride in 50 ml of acetone wasslowly added under stirring over a period of 30 min. The acetone wasevaporated and the aqueous phase was extracted 3 times with ethylacetate to yield the crude title compound as a slightly brown solid.

MS (m/e): 287.1 (M−H, 43%)

(b) 2-(4-Bromo-phenyl)-oxazole

A solution of 21 mmol of phosphorous pentoxide in 20 ml ofmethylsulfonic acid was treated with 7 mmol of4-Bromo-N-(2,2-dimethoxy-ethyl)-benzamide. The reaction mixture washeated for 5 hours at 130°, cooled to room temperature and poured intoice-water. The resulting solid was filtered off and dried to yield thecrude title compound as a brownish solid. MS (m/e): 224.0 (MH⁺, 24%)

(c) 4-(4-Oxazol-2-yl-phenyl)-piperazine-1-carboxylic acid tert-butylester

Prepared in analogy to example 4.4 (a) from 2-(4-Bromo-phenyl)-oxazoleand N-BOC -piperazine. MS (m/e): 330.3 (MH⁺, 100%)

(d) 1-(4-Oxazol-2-yl-phenyl)-piperazine hydrochloride

Prepared in analogy to example 4.4 (b) from4-(4-Oxazol-2-yl-phenyl)-piperazine-1-carboxylic acid tert-butyl esterand hydrochloric acid in dioxane. MS (m/e): 230.1 (MH⁺, 100%)

EXAMPLE 4.6 Preparation of1-[4-(5-Methyl-[1,3,4]oxadiazol-2-yl)-phenyl]-piperazine hydrochloride

(a) 2-(4-Bromo-phenyl)-[1,3,4]oxadiazole

12.3 mmol of 4-bromo-benzoic acid hydrazide were dissolved in 26 ml oftriethyl orthoformate. The reaction mixture was stirred overnight at140°, evaporated and the residue crystallized from ethanol to give thetitle compound as a colorless solid. MS (m/e): 225.0 (MH⁺, 100%)

(b) 4-(4-[1,3,4]Oxadiazol-2-yl-phenyl)-piperazine-1-carboxylic acidtert-butyl ester

Prepared in analogy to example 4.4 (a) from2-(4-Bromo-phenyl)-[1,3,4]oxadiazole and N-BOC-piperazine.

MS (m/e): 342.2 (MH⁺, 100%)

(c) 1-[4-(5-Methyl-[1.3,4]oxadiazol-2-yl)-phenyl]-piperazinehydrochloride

Prepared in analogy to example 4.4 (b) from4-(4-[1,3,4]Oxadiazol-2-yl-phenyl)-piperazine-1-carboxylic acidtert-butyl ester and hydrochloric acid in dioxane. MS (m/e): 245.3 (MH⁺,100%)

EXAMPLE 4.7 Preparation of1-[4-(2-Methyl-2H-tetrazol-5-yl)-phenyl]-piperazine hydrochloride

(a) 5-(4-Bromo-phenyl)-2-methyl-2H-tetrazole

A mixture of 3.5 mmol of 5-(4-bromo-phenyl)-2H-tetrazole, 0.2 mmol oftetrabutyl ammonium bromide, 4.4 mmol of methyl iodide, 6 ml of 1Maqueous sodium hydroxide and 6 ml of dichloromethane were stirred atroom temperature for 24 hours. The reaction mixture was diluted withwater and extracted with ethyl acetate. The organic phase was dried,evaporated and the product purified by column chromatography (SiO₂;cyclohexane/ethyl acetate 7:3). MS (m/e): 239.1 (MH⁺, 29%)

(b) 4-[4-(2-Methyl-2H-tetrazol-5-yl)-phenyl]-piperazine-1-carboxylicacid tert-butyl ester

Prepared in analogy to example 4.4 (a) from5-(4-Bromo-phenyl)-2-methyl-2H-tetrazole and N-BOC-piperazine. MS (m/e):345.1 (MH⁺, 41%)

(c) 1-[4-(2-Methyl-2H-tetrazol-5-yl)-phenyl]-piperazine hydrochloride

Prepared in analogy to example 4.4 (b) from4-[4-(2-Methyl-2H-tetrazol-5-yl)-phenyl]-piperazine-1-carboxylic acidtert-butyl ester and hydrochloric acid in dioxane. MS (m/e): 245.1 (MH⁺,100%)

EXAMPLE 4.8 Preparation of3,4,5,6-Tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid methyl esterhydrochloride

(a) 2,3,5,6-Tetrahydro-[1,2′]bipyrazinyl-4,5′-dicarboxylic acid4-tert-butyl ester 5′-methyl ester

A mixture of 17 mmol methyl-5-chloropyrazine-2-carboxylate, 18 mmol ofN-BOC-piperazine and 20 mmol of K₂CO₃ in 20 ml of acetonitrile washeated under reflux for 3 hours. The reaction mixture was concentrated,diluted with water and extracted with ethyl acetate. The title compoundwas recrystallized from ethyl acetate to yield a colorless solid. MS(m/e): 323.4 (MH⁺, 100%)

(b) 3,4,5,6-Tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid methylester hydrochloride

Prepared in analogy to example 4.4 (b) from2,3,5,6-Tetrahydro-[1,2′]bipyrazinyl-4,5′-dicarboxylic acid 4-tert-butylester 5′-methyl ester and 1,4-dioxane saturated with gaseous HCl. MS(m/e): 223.1 (MH⁺, 100%)

EXAMPLE 4.9 Preparation of6′-Chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl trifluoroacetate

(a) 6′-Chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acidtert-butyl ester

A mixture of 10 mmol 2,6-dichloropyrazine and 21 mmol ofN-BOC-piperazine in 15 ml acetonitrile was heated under reflux for 1.5hours. The reaction mixture was concentrated and purified bychromatography (SiO₂; dichloromethane/methanol 95:5) to yield the titlecompound as a colorless solid. MS (m/e): 299.2 (MH⁺, 100%)

(b) 6′-Chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl trifluoroacetate

A solution of 2 mmol6′-Chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acidtert-butyl ester in 10 ml of dichloromethane was treated with 3 mmol oftrifluoroacetic acid and stirred at room temperature for 17 hours.Concentration and crystallisation from diethylether yielded the titlecompound as a colorless solid. MS (m/e): 198.0 (M⁺, 100%)

EXAMPLE 4.10 Preparation of3,4,5,6-Tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid amidehydrochloride

(a) 5′-Carbamoyl-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acidtert-butyl ester

3 mmol of 2,3,5,6-Tetrahydro-[1,2′]bipyrazinyl-4,5′-dicarboxylic acid4-tert-butyl ester 5′-methyl ester (example 1.13 (a)) was dissolved in a7 molar solution of gaseous ammonia in methanol. The reaction vessel wastightly closed and heated overnight at 60° C. Cooling of the reactionmixtures led to crystallisation of the title compound. MS (m/e): 308.4(MH⁺, 100%)

(b) 3,4,5,6-Tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid amidehydrochloride

0.25 mmol of5′-Carbamoyl-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acidtert-butyl ester was stirred for 1 hour in 1 ml of dioxane saturatedwith gaseous HCl. Concentration of the reaction mixture led to the titlecompound, as a colorless solid. MS (m/e): 208.3 (MH⁺, 100%)

EXAMPLE 4.11 Preparation ofDimethyl-(4-piperazin-1-yl-[1,3,5]triazin-2-yl)-amine

(a) 4-(4-Chloro-[1,3,5]triazin-2-yl)-piperazine-1-carboxylic acidtert-butyl ester

A solution of 11 mmol of 2,4-dichlorotriazine (WO 02/083654) in 20 ml ofacetonitrile was chilled and treated with 11 mmol of triethylamine and11 mmol of N-BOC-piperazine. The reaction mixture was stirred for 2hours at 0° C. then for 2 hours at room temperature. Addition of 100 mlbrine and extraction with ethyl acetate yielded the crude product whichwas purified through trituration in ethyl acetate. MS (m/e): 300.3 (MH⁺,100%)

(b) 4-(4-Dimethylamino-[1,3,5]triazin-2-yl)-piperazine-1-carboxylic acidtert-butyl ester

A solution of 2 mmol of4-(4-Chloro-[1,3,5]triazin-2-yl)-piperazine-1-carboxylic acid tert-butylester in 15 ml of 2M dimethylamine in methanol was stirred at roomtemperature for 1 hour. Concentration and purification by chromatography(SiO₂; ethyl acetate/cyclohexane 1:1) yielded the title compound as acolorless solid. MS (m/e): 309.1 (MH⁺, 100%)

(c) Dimethyl-(4-piperazin-1-yl-[1,3,5]triazin-2-yl)-amine

A solution of 1 mmol of4-(4-Dimethylamino-[1,3,5]triazin-2-yl)-piperazine-1-carboxylic acidtert-butyl ester in 10 ml dichloromethane was chilled and treated with14 mmol of trifluoroacetic acid. The reaction mixture was heated to 40°C. for 30 min. After cooling, 50 ml of 2M aqueous sodium hydroxide wasadded. The organic layer was separated, dried and concentrated to yieldthe title compound as a yellowish oil. MS (m/e): 267.0 (M+CH₃COO⁺, 100%)

EXAMPLE 4.12 Preparation of6′-Methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl

(a) 6′-Methoxy-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acidtert-butyl ester

1 mmol of 6′-Chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylicacid tert-butyl ester [example 4.9 (a)] was dissolved in a solution ofsodium methanolate (prepared by dissolving 1 mmol of sodium in 10 ml ofmethanol). The mixture was heated overnight to 70°, concentrated and theproduct purified by chromatography (SiO₂; dichloromethane/methanol 99:1)to yield the title compound as a colorless foam. MS (m/e): 295.3 (MH⁺,100%)

(b) 6′-Methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl

Prepared in analogy to example 4.10 (c) from6′-Methoxy-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acidtert-butyl ester and trifluoroacetic acid. MS (m/e): 195.1 (MH⁺, 80%)

EXAMPLE 4.13 Preparation of 2-Methoxy-4-piperazin-1-yl-[1,3,5]triazine

(a) 4-(4-Methoxy-[1,3,5]triazin-2-yl)-piperazine-1-carboxylic acidtert-butyl ester

1 mmol of 4-(4-Chloro-[1,3,5]triazin-2-yl)-piperazine-1-carboxylic acidtert-butyl ester [example 4.11 a)] was dissolved in a solution of sodiummethanolate (prepared by dissolving 1 mmol of sodium in 5 ml ofmethanol). The mixture was stirred at room temperature for 1 hour,concentrated and the title compound purified by recrystallisation fromethyl acetate/cyclohexane. MS (m/e): 296.3 (MH⁺, 100%)

(b) 2-Methoxy-4-piperazin-1-yl-[1,3,5]triazine

Prepared in analogy to example 4.10 (c) from4-(4-Methoxy-[1,3,5]triazin-2-yl)-piperazine-1-carboxylic acidtert-butyl ester and trifluoroacetic acid. MS (m/e): 196.4 (MH⁺, 100%)

EXAMPLE 4.14 Preparation of2-Dimethylcarbamoyloxy-5-methanesulfonyl-benzoic acid

(a) 2-Hydroxy-5-methanesulfonyl-benzoic acid benzyl ester

5 mmol of N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimid-hydrochloridewas slowly added to a stirred suspension of 5 mmol2-hydroxy-5-methanesulfonyl-benzoic acid, 5 mmol of benzyl alcohol and0.5 mmol of 4-dimethylaminopyridine in 10 ml acetonitrile. The mixturewas stirred overnight at room temperature, concentrated and treated with10 ml of water. A few drops of diluted hydrochloric acid were added toacidify the solution. The resulting solid was filtered and then purifiedby chromatography (SiO₂; ethyl acetate/cyclohexane 3:7) to yield thetitle compound as a colorless solid. MS (m/e): 305.0 (M−H, 100%)

(b) 2-Dimethylcarbamoyloxy-5-methanesulfonyl-benzoic acid benzyl ester

A mixture of 1 mmol 2-hydroxy-5-methanesulfonyl-benzoic acid benzylester, 1.5 mmol of N-methylmorpholine and 0.2 mmol of4-dimethylaminopyridine in 4 ml of dimethylformamide was treated with1.3 mmol of N,N-dimethyl-carbamoylchloride. The reaction mixture wasstirred at 60° for 48 hours, concentrated in vacuo and the residue takenup in 5 ml of water. Acidification with diluted hydrochloric acid andextraction with ethyl acetate yielded a crude product which was purifiedby chromatography (SiO₂; ethyl acetate/cyclohexane 1.1). MS (m/e): 378.3(MH⁺, 100%)

(c) 2-Dimethylcarbamoyloxy-5-methanesulfonyl-benzoic acid

1 mmol of 2-dimethylcarbamoyloxy-5-methanesulfonyl-benzoic acid benzylester was dissolved in 5 ml of methanol. 25 mg of palladium 10% oncharcoal was added and the reaction mixture hydrogenated at roomtemperature to yield the title compound as a slightly yellowish solid.MS (m/e): 288.0 (MH⁺, 66%)

In analogy to Example 5 compounds 327 to 355 of the following table wereprepared from the acid derivatives and piperazine derivatives:

Expl. MW found No. Systematic Name Starting materials (MH⁺) 327(6-Ethoxy-2-fluoro-3- 1-(4-Methanesulfonyl-phenyl)- 485.4methanesulfonyl- piperazine (commercial) and phenyl)-[4-(4-6-Ethoxy-2-fluoro-3- methanesulfonyl- methanesulfonyl-benzoic acidphenyl)-piperazin-1- (compound 4.1) yl]-methanone 328 (2-Isopropoxy-5-1-(4-Trifluoromethanesulfonyl- 552.0 methanesulfonyl- phenyl)-piperazine(M + NH₄ ⁺) phenyl)-[4-(4- (compound 4.2) and 2-trifluoromethanesulfonyl- Isopropoxy-5- phenyl)-piperazin-1-yl]-methanesulfonyl-benzoic acid methanone (compound 1.2) 329(2-Cyclopentyloxy-5- 1-(4-Trifluoromethanesulfonyl- 578.0methanesulfonyl- phenyl)-piperazine (M + NH₄ ⁺) phenyl)-[4-(4- (compound4.2) and 2- trifluoromethanesulfonyl- Cyclopentyloxy-5-methanesulfonyl-phenyl)-piperazin-1-yl]- benzoic acid (compound 1.6) methanone 330(2-Isobutoxy-5- 1-(4-Trifluoromethanesulfonyl- 566.1 methanesulfonyl-phenyl)-piperazine (M + NH₄ ⁺) phenyl)-[4-(4- (compound 4.2) and 2-trifluoromethanesulfonyl- Isobutoxy-5-methanesulfonyl-phenyl)-piperazin-1-yl]- benzoic acid (compound 1.3) methanone 331[4-(2,4-Bis- 1-(2,4-Bis-trifluoromethyl- 539.2 trifluoromethyl-phenyl)-piperazine phenyl)-piperazin-1- hydrochloride (compound 4.3)yl]-(2-isopropoxy-5- and 2-Isopropoxy-5- methanesulfonyl-methanesulfonyl-benzoic acid phenyl)-methanone (compound 1.2) 332[4-(2,4-Bis- 1-(2,4-Bis-trifluoromethyl- 565.3 trifluoromethyl-phenyl)-piperazine phenyl)-piperazin-1- hydrochloride (compound 4.3)yl]-(2-cyclopentyloxy- and 2-Cyclopentyloxy-5- 5-methanesulfonyl-methanesulfonyl- phenyl)-methanone benzoic acid (compound 1.6) 333[4-(2,4-Bis- 1-(2,4-Bis-trifluoromethyl- 553.2 trifluoromethyl-phenyl)-piperazine phenyl)-piperazin-1- hydrochloride (compound 4.3)yl]-(2-isobutoxy-5- and 2-Isobutoxy-5- methanesulfonyl-methanesulfonyl-benzoic acid phenyl)-methanone (compound 1.3) 334(2-Isobutoxy-5- 1-[4-(5-Methyl- 499.1 methanesulfonyl-[1,2,4]oxadiazol-3-yl)-phenyl]- phenyl)-{4-[4-(5- piperazinehydrochloride methyl- (compound 4.4) and 2- [1,2,4]oxadiazol-3-yl)-Isobutoxy-5-methanesulfonyl- phenyl]-piperazin-1- benzoic acid (compound1.3) yl}-methanone 335 (2-Cyclopentyloxy-5- 1-[4-(5-Methyl- 511.4methanesulfonyl- [1,2,4]oxadiazol-3-yl)-phenyl]- phenyl)-{4-[4-(5-piperazine hydrochloride methyl- (compound 4.4) and 2-[1,2,4]oxadiazol-3-yl)- Cyclopentyloxy-5- phenyl]-piperazin-1-methanesulfonyl- yl}-methanone benzoic acid (compound 1.6) 336(2-Isobutoxy-5- 1-(4-Oxazol-2-yl-phenyl)- 484.4 methanesulfonyl-piperazine; hydrochloride phenyl)-[4-(4-oxazol- (compound 4.5) and 2-2-yl-phenyl)- Isobutoxy-5-methanesulfonyl- piperazin-1-yl]- benzoic acid(compound 1.3) methanone 337 (2-Cyclopentyloxy-5-1-(4-Oxazol-2-yl-phenyl)- 496.4 methanesulfonyl- piperazine;hydrochloride phenyl)-[4-(4-oxazol- (compound 4.5) and 2- 2-yl-phenyl)-Cyclopentyloxy-5- piperazin-1-yl]- methanesulfonyl- methanone benzoicacid (compound 1.6) 338 (2-Isopropoxy-5- 1-[4-(5-Methyl-[1,3,4] 485.3methanesulfonyl- oxadiazol-2-yl)-phenyl]- phenyl)-{4-[4-(5- piperazinehydrochloride methyl- (compound 4.6) and 2- [1,3,4]oxadiazol-2-yl)-Isopropoxy-5-methane phenyl]-piperazin-1- sulfonyl-benzoic acidyl}-methanone (compound 1.2) 339 (2-Isobutoxy-5- 1-[4-(5-Methyl-[1,3,4]499.2 methanesulfonyl- oxadiazol-2-yl)-phenyl]- phenyl)-{4-[4-(5-piperazine hydrochloride methyl- (compound 4.6) and 2-[1,3,4]oxadiazol-2-yl)- Isobutoxy-5-methanesulfonyl-phenyl]-piperazin-1- benzoic acid (compound 1.3) yl}-methanone 340(2-Cyclopentyloxy-5- 1-[4-(5-Methyl- 511.3 methanesulfonyl-[1,3,4]oxadiazol-2-yl)-phenyl]- phenyl)-{4-[4-(5- piperazinehydrochloride methyl- (compound 4.6) and 2- [1,3,4]oxadiazol-2-yl)-Cyclopentyloxy-5- phenyl]-piperazin-1- methanesulfonyl- yl}-methanonebenzoic acid (compound 1.6) 341 (2-Isobutoxy-5-1-[4-(2-Methyl-2H-tetrazol-5- 499.1 methanesulfonyl-yl)-phenyl]-piperazine; phenyl)-{4-[4-(2- hydrochloride (compoundmethyl-2H!-tetrazol- 4.7) and 2-Isobutoxy-5- 5-yl)-phenyl]-methanesulfonyl-benzoic acid piperazin-1-yl}- (compound 1.3) methanone342 4-(2-Isopropoxy-5- 3,4,5,6-Tetrahydro-2H- 463.4 methanesulfonyl-[1,2′]bipyrazinyl-5′-carboxylic benzoyl)-3,4,5,6- acid methyl ester;tetrahydro-2H- hydrochloride (compound [1,2′]bipyrazinyl-5′- 4.8) and2-Isopropoxy-5- carboxylic acid methyl methanesulfonyl-benzoic acidester (compound 1.2) 343 4-(2-Isobutoxy-5- 3,4,5,6-Tetrahydro-2H- 477.1methanesulfonyl- [1,2′]bipyrazinyl-5′-carboxylic benzoyl)-3,4,5,6- acidmethyl ester; tetrahydro-2H- hydrochloride (compound[1,2′]bipyrazinyl-5′- 4.8) and 2-Isobutoxy-5- carboxylic acid methylmethanesulfonyl-benzoic acid ester (compound 1.3) 344(6′-Chloro-2,3,5,6- 6′-Chloro-3,4,5,6-tetrahydro- 439.1 tetrahydro-2H-[1,2′]bipyrazinyl; trifluoro- [1,2′]bipyrazinyl-4- acetic acid(compound 4.9) yl)-(2-isopropoxy-5- and 2-Isopropoxy-5- methanesulfonyl-methanesulfonyl-benzoic acid phenyl)-methanone (compound 1.2) 3454-(2-Isopropoxy-5- 3,4,5,6-Tetrahydro-2H- 448.3 methanesulfonyl-[1,2′]bipyrazinyl-5′-carboxylic benzoyl)-3,4,5,6- acid amide;hydrochloride tetrahydro-2H- (compound 4.10) and 2-[1,2′]bipyrazinyl-5′- Isopropoxy-5-methanesulfonyl- carboxylic acidamide benzoic acid (compound 1.2) 346 4-(2-Isobutoxy-5-3,4,5,6-Tetrahydro-2H- 462.3 methanesulfonyl-[1,2′]bipyrazinyl-5′-carboxylic benzoyl)-3,4,5,6- acid amide;hydrochloride tetrahydro-2H- (compound 4.10) and 2-[1,2′]bipyrazinyl-5′- Isobutoxy-5-methanesulfonyl- carboxylic acid amidebenzoic acid (compound 1.3) 347 [4-(4-Dimethylamino-Dimethyl-(4-piperazin-1-yl- 463.3 [1,3,5]triazin-2-yl)-[1,3,5]triazin-2-yl)-amine piperazin-1-yl]-(2- (compound 4.11) and 2-isobutoxy-5- Isobutoxy-5-methanesulfonyl- methanesulfonyl- benzoic acid(compound 1.3) phenyl)-methanone 348 [4-(4-Dimethylamino-Dimethyl-(4-piperazin-1-yl- 449.3 [1,3,5]triazin-2-yl)-[1,3,5]triazin-2-yl)-amine piperazin-1-yl]-(2- (compound 4.11) and 2-isopropoxy-5- Isopropoxy-5-methane methanesulfonyl- sulfonyl-benzoicacid phenyl)-methanone (compound 1.2) 349 (2-Isopropoxy-5-6′-Methoxy-3,4,5,6-tetrahydro- 435.2 methanesulfonyl-2H-[1,2′]bipyrazinyl; trifluoro- phenyl)-(6′-methoxy- acetic acid(compound 4.12) 2,3,5,6-tetrahydro- and 2-Isopropoxy-5-methanesulfonyl-[1,2′]bipyrazinyl-4- benzoic acid (compound 1.2) yl)-methanone 350(2-Isopropoxy-5- 2-Methoxy-4-piperazin-1-yl- 436.4 methanesulfonyl-[1,3,5]triazine (compound phenyl)-[4-(4-methoxy- 4.13) and2-Isopropoxy-5- [1,3,5]triazin-2-yl)- methanesulfonyl-benzoic acidpiperazin-1-yl]- (compound 1.2) methanone 351 Dimethyl-carbamic1-(4-Trifluoromethyl-phenyl)- 500.4 acid 4-methanesulfonyl- piperazine(commercial) and 2-[4-(4-trifluoromethyl- 2-Dimethylcarbamoyloxy-5-phenyl)-piperazine-1- methanesulfonyl-benzoic acid carbonyl]-phenylester (compound 4.14) 352 Dimethyl-carbamic 1-(2-Fluoro-4-methane 528.3acid 2-[4-(2-fluoro-4- sulfonyl-phenyl)-piperazine methanesulfonyl-(commercial) and 2- phenyl)-piperazine-1- Dimethylcarbamoyloxy-5-carbonyl]-4- methanesulfonyl-benzoic acid methanesulfonyl- (compound4.14) phenyl ester 353 (2-Cyclopropylmethoxy- 1-Phenyl-piperazine 415.55-methanesulfonyl- (commercial) and 2- phenyl)-(4- Cyclopropylmethoxy-5-phenyl-piperazin-1- methanesulfonyl-benzoic acid yl)-methanone (compound1.4) 354 (2-Cyclopropylmethoxy- 1-(4-Methoxy-phenyl)- 445.35-methanesulfonyl- piperazine (commercial) and phenyl)-[4-(4-2-Cyclopropylmethoxy-5- methoxy-phenyl)- methanesulfonyl-benzoic acidpiperazin-1-yl]- (compound 1.4) methanone 355 (2-Cyclopropylmethoxy-4-Piperazin-1-yl-phenol 431.4 5-methanesulfonyl- (commercial) and 2-phenyl)-[4-(4- Cyclopropylmethoxy-5- hydroxy-phenyl)-methanesulfonyl-benzoic acid piperazin-1-yl]- (compound 1.4) methanone

EXAMPLE 356 Preparation of1-{3-Fluoro-4-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-phenyl}-ethanoneoxime

0.12 mmol of1-{3-Fluoro-4-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-phenyl}-ethanonewas dissolved in 1 ml of a 1:1 mixture of ethanol and water. 0.8 mmol ofhydroxylamine hydrochloride was added, followed by 8.4 mmol of sodiumacetate. The resulting mixture was stirred overnight at roomtemperature, diluted with water, filtered, washed and dried to yield thetitle compound as a colorless solid.

MS (m/e): 478.2 (MH⁺, 100%)

EXAMPLE 357 Preparation of1-{3-Fluoro-4-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-phenyl}-ethanoneO-methyl-oxime

0.12 mmol of1-{3-Fluoro-4-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-phenyl}-ethanonewas dissolved in 1 ml of a 1:1 mixture of ethanol and water. 0.8 mmol ofO-methyl-hydroxylamine hydrochloride was added, followed by 8.4 mmol ofsodium acetate. The slurry was stirred overnight at room temperature,diluted with water, extracted with ethyl acetate, dried andconcentrated. The resulting gum was triturated with diethylether/heptane to yield the title compound as a colorless solid. MS(m/e): 492.3 (MH⁺, 100%)

EXAMPLE 4.15 Preparation of(2,6-Difluoro-3-methanesulfonyl-phenyl)-[4-(2-fluoro-4-methanesulfonyl-phenyl)-piperazin-1-yl]-methanone

(a) 3-Chlorosulfonyl-2,6-difluoro-benzoic acid

77 mmol of 2,6-difluorobenzoic acid were dissolved in 15.5 ml ofchlorosulfonic acid and stirred for 2 h at 150° C. The reaction mixturewas cooled to room temperature and poured into 100 ml of ice/water. Thesolid was filtered and dried to yield the title compound as a colorlesssolid. MS (m/e): 255.1 (M−H, 44%)

(b) 2,6-Difluoro-3-sulfino-benzoic acid

240 mmol of sodium sulfite were dissolved in 150 ml of water. 32 mmol of3-Chlorosulfonyl-2,6-difluoro-benzoic acid was added under stirring overa period of about 20 min. After stirring for an additional hour at roomtemperature, the mixture was chilled and acidified with 20% aqueoussulfuric acid. The product was extracted with ethyl acetate to yield thetitle compound as a colorless solid. MS (m/e): 221.3 (M−H, 34%)

(c) 2,6-Difluoro-3-methanesulfonyl-benzoic acid

A suspension of 18 mmol sodium carbonate and 9 mmol2,6-Difluoro-3-sulfino-benzoic acid in 30 ml of methanol was stirred atroom temperature for 30 min, then heated to 60° C. 24 mmol of methyliodide were added and the reaction mixture heated overnight at 60° C.The reaction mixture was diluted with water and extracted with ethylacetate. The organic phase was discarded and the aqueous phase acidifiedby addition of concentrated hydrochloric acid. Extraction with ethylacetate yielded the title compound as a slightly brownish solid. MS(m/e): 235.1 (M−H, 16%)

(d)(2,6-Difluoro-3-methanesulfonyl-phenyl)-[4-(2-fluoro-4-methanesulfonyl-phenyl)-piperazin-1-yl]-methanone

This compound was prepared in analogy to example 5 from1-(2-fluoro-4-methanesulfonyl-phenyl)-piperazine and2,6-difluoro-3-methanesulfonyl-benzoic acid. MS (m/e): 477.0 (MH⁺, 67%)

EXAMPLE 4.16 Preparation of4-[4-(2,6-Difluoro-3-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile

Prepared in analogy to example 5 from 4-piperazin-1-yl-benzonitrile and2,6-difluoro-3-methanesulfonyl-benzoic acid. MS (m/e): 406.3 (MH⁺, 84%)

EXAMPLE 358 Preparation of(2-Cyclopentyloxy-6-ethoxy-3-methanesulfonyl-phenyl)-[4-(4-methanesulfonyl-phenyl)-piperazin-1-yl]-methanone

0.12 mmol of(6-Ethoxy-2-fluoro-3-methanesulfonyl-phenyl)-[4-(4-methanesulfonyl-phenyl)-piperazin-1-yl]-methanone(example 55) was added to a solution of sodium cyclopentanolate(prepared from 1 mmol sodium dissolved in 1 ml of cyclopentanol). Themixture was heated for 1 hour at 80° C., poured on ice/water andextracted with ethyl acetate. Chromatography (SiO₂; ethyl acetate)yielded the title compound as a slightly yellow solid. MS (m/e): 551.1(MH⁺, 29%)

EXAMPLE 359 Preparation of(2,6-diisopropoxy-3-methanesulfonyl-phenyl)-[4-(2-fluoro-4-methanesulfonyl-phenyl)-piperazin-1-yl]-methanone

0.27 mmol of2,6-difluoro-3-methanesulfonyl-phenyl)-[4-(2-fluoro-4-methanesulfonyl-phenyl)-piperazin-1-yl]-methanone(example 4.15) was added to a solution of sodium isopropanolate(prepared by dissolving 3 mmol of sodium in 2 ml of isopropanol). Thereaction mixture was heated under reflux for 5 hours, cooled, dilutedwith water and extracted with ethyl acetate, yielding the title compoundas a slightly yellow solid. MS (m/e): 557.3 (MH⁺, 66%)

EXAMPLE 360 Preparation of(2-Fluoro-6-isopropoxy-3-methanesulfonyl-phenyl)-[4-(2-fluoro-4-methanesulfonyl-phenyl)-piperazin-1-yl]-methanone

0.2 mmol of(2,6-difluoro-3-methanesulfonyl-phenyl)-[4-(2-fluoro-4-methanesulfonyl-phenyl)-piperazin-1-yl]-methanonewere dissolved in a solution of sodium isopropanolate (prepared bydissolving 0.2 mmol of sodium in 1 ml of isopropanol). The reactionmixture was heated to 50° C. for 2 hours, then stirred at roomtemperature for 48 hours. The solution was diluted with water andextracted with ethyl acetate. The product was purified by chromatography(SiO₂, ethyl acetate/cyclohexane 9:1) to yield the title compound as acolorless solid. MS (m/e): 517.1 (MH⁺, 100%)

EXAMPLE 361 Preparation of(6-Cyclopentyloxy-2-fluoro-3-methanesulfonyl-phenyl)-[4-(2-fluoro-4-methanesulfonyl-phenyl)-piperazin-1-yl]-methanone

The compound was prepared in analogy to example 358 from(2,6-difluoro-3-methanesulfonyl-phenyl)-[4-(2-fluoro-4-methanesulfonyl-phenyl)-piperazin-1-yl]-methanoneand sodium cyclopentanolate. MS (m/e): 560.5 (MNH₄ ⁺, 43%)

EXAMPLE 362 Preparation of4-[4-(2-Fluoro-6-isopropoxy-3-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile

The compound was prepared in analogy to example 359 from4-[4-(2,6-difluoro-3-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrileand sodium isopropanolate. MS (m/e): 446.0 (MH⁺, 49%)

EXAMPLE 5.1 Preparation of1-(3-Fluoro-4-trifluoromethyl-phenyl)-piperazine

(a) 4-(3-Fluoro-4-trifluoromethyl-phenyl)-piperazine-1-carboxylic acidtert-butyl ester

A mixture of 4.9 mmol 4-chloro-2-fluorobenzotrifluoride, 5.9 mmoln-Boc-piperazine, 0.05 mmol palladium acetate, 6.9 mmolsodium-t-butoxide and 0.49 mmol 2-(di-t-butylphosphino)biphenyl in 10 mltoluene was heated for 16 h at 80° C. After cooling to RT, the mixturewas diluted with ether; the suspension was filtered over decalite; andthe filtrate evaporated. The residue was purified on silica eluting witha gradient of heptane/EtOAc to yield after evaporation the titlecompound.

(b) 1-(3-Fluoro-4-trifluoromethyl-phenyl)-piperazine

A mixture of 2.87 mmol4-(3-Fluoro-4-trifluoromethyl-phenyl)-piperazine-1-carboxylic acidtert-butyl ester in 10 ml dichloromethane was treated with 14.4 mmoltrifluoroacetic acid and refluxed for 3 h. The mixture was concentratedand treated with 10 ml water, NaOH and extracted with dichloromethane.The combined organic phases were dried with MgSO₄ and evaporated toyield the title compound 5.1. MS (m/e): 249.2 (MH⁺, 100%)

EXAMPLE 5.2 Preparation of2-Piperazin-1-yl-5-trifluoromethyl-benzonitrile

The compound was prepared in analogy to compound 5.1 from2-Chloro-5-trifluoromethyl-benzonitrile (DE2550262). MS (m/e): 256.0(MH⁺, 100%)

EXAMPLE 5.3 Preparation of1-(2,3-Difluoro-4-methanesulfonyl-phenyl)-piperazine

The compound was prepared in analogy to compound 2.20 from2,3,4-Trifluoro-benzenesulfonyl chloride (commercial). MS (m/e): 277.2(MH⁺, 100%)

EXAMPLE 5.4 Preparation of 1-(2-Fluoro-4-methyl-phenyl)-piperazine

The compound was prepared in analogy to compound 1.1 from4-bromo-3-fluorotoluene (commercial). MS (m/e): 195.3 (MH⁺, 100%)

EXAMPLE 5.5 Preparation of1-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazine

The compound was prepared in analogy to compound 2.7 from2,3-Difluoro-5-trifluoromethyl-pyridine (EP0104715). MS (m/e): 250.2(MH⁺, 100%)

EXAMPLE 5.6 Preparation of5-Methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid

(a) rac-5-Methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoicacid methyl ester

A mixture of 21.7 mmol 2-Hydroxy-5-methanesulfonyl-benzoic acid methylester [68029-77-6], 32.5 mmol trifluoro-methanesulfonic acid2,2,2-trifluoro-1-methyl-ethyl ester [212556-43-9], 43.4 mmol potassiumcarbonate in 87 ml DMF was stirred at 80° C. for 48 hours. After coolingto RT, the mixture was concentrated in vacuo, taken in water and stirredfor 1 hour. Filtration yielded the title compound.

(b) 5-Methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoicacid methyl ester

The title compound was obtained by separation ofrac-5-Methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acidmethyl ester by chiral HPLC (Chiralcel OD, 15% ethanol/Heptane, flow 35ml, 220 nm, retention time: 86 min.).

(c) 5-Methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoicacid

The compound was prepared in analogy to compound 2.10(b) from5-Methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acidmethyl ester MS (m/e): 311.0 (M−H, 100%)

EXAMPLE 5.7 Preparation of5-Methanesulfonyl-2-((R)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid

(a) 5-Methanesulfonyl-2-((R)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoicacid methyl ester

The title compound was obtained by separation ofrac-5-Methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acidmethyl ester by chiral HPLC (Chiralcel OD, 15% ethanol/Heptane, flow 35ml, 220 nm, retention time: 74 min.).

(b) 5-Methanesulfonyl-2-((R)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoicacid

The compound was prepared in analogy to compound 2.10(b) from5-Methanesulfonyl-2-((R)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acidmethyl ester MS (m/e): 311.0 (M−H, 100%)

EXAMPLE 5.8 Preparation of 2-Chloro-4-piperazin-1-yl-benzonitrile

A mixture of 7.0 mmol 2-chloro-4-fluorobenzonitrile (commercial), 10.5mmol piperazine in 4 ml N,N-dimethylacetamide was heated for 1 h at 85°C. After cooling to RT and evaporation in vacuo, the mixture was dilutedwith dichloromethane and purified on silica, eluting with a gradient ofdichloromethane/MeOH to yield after evaporation the title compound. MS(m/e): 222.1 (MH⁺, 100%)

EXAMPLE 5.9 Preparation of 1-(2-Fluoro-4-piperazin-1-yl-phenyl)-ethanone

The compound was prepared in analogy to compound 5.8 from2,4-difluoroacetophenone (commercial). MS (m/e): 223.2 (M−H, 100%)

EXAMPLE 5.10 Preparation of1-(3-Fluoro-4-methanesulfonyl-phenyl)-piperazine

The compound was prepared in analogy to compound 2.20 from2,4-difluorobenzenesulfonylchloride (commercial). MS (m/e): 259.1 (MH⁺,100%)

EXAMPLE 5.11 Preparation of1-(4-Fluoro-2-piperazin-1-yl-phenyl)-ethanone

The compound was prepared in analogy to compound 5.8 from2,4-difluoroacetophenone (commercial). MS (m/e): 223.2 (M−H, 100%)

EXAMPLE 5.12 Preparation of 6-Isopropoxy-isophthalamic acid

The compound was prepared in analogy to compound 2.10 from6-Hydroxy-isophthalamic acid methyl ester [89366-34-7]. MS (m/e): 222.1(M−H, 100%)

EXAMPLE 5.13 Preparation of 5-Ethanesulfonyl-2-isopropoxy-benzoic acid

(a) 5-Ethanesulfonyl-2-hydroxy-benzoic acid methyl ester

The compound was prepared in analogy to compound 2.20(b) from2-Hydroxy-5-sulfino-benzoic acid [19479-88-0] and ethyliodide

(b) 5-Ethanesulfonyl-2-isopropoxy-benzoic acid

The compound was prepared in analogy to compound 2.10 from5-Ethanesulfonyl-2-hydroxy-benzoic acid methyl ester. MS (m/e): 271.1(M−H, 100%)

EXAMPLE 5.14 Preparation of1-(4-Difluoromethyl-2-fluoro-phenyl)-piperazine

(a) 1-Chloro-4-difluoromethyl-2-fluoro-benzene

24.7 mmol 4-Chloro-3-fluorobenzaldehyde was dissolved in DAST (5.1 ml)under nitrogen. The mixture was stirred at room temperature for 3 hours,at 50° C. for 2 hours and then at room temperature for 65 hours. Thesolution was added dropwise to a saturated.bicarbonate solution (150 ml)under cooling. The aqueous layer was extracted 3 times with ethylacetate. The combined extracts were dried over Na₂SO₄, filtered and thesolvent was removed in vacuo. The residue was purified on silica elutingwith heptane to yield after evaporation the title compound.

(b) 1-(4-Difluoromethyl-2-fluoro-phenyl)-piperazine

The compound was prepared in analogy to compound 1.1 from1-Chloro-4-difluoromethyl-2-fluoro-benzene. MS (m/e): 231.2 (M+H⁺, 100%)

EXAMPLE 5.15 Preparation of1-(6-Trifluoromethyl-pyridin-3-yl)-piperazine

The compound was prepared in analogy to compound 1.1 from5-Bromo-2-trifluoromethyl-pyridine [436799-32-5]. MS (m/e): 232.1 (M+H⁺,100%)

EXAMPLE 5.16 Preparation of 3-Fluoro-4-piperazin-1-yl-benzoic acid ethylester

The compound was prepared in analogy to compound 5.8 fromEthyl-3,4-difluorobenzoate (commercial). MS (m/e): 253.2 (M+H⁺, 100%)

EXAMPLE 5.17 Preparation of1-(2-Trifluoromethyl-pyridin-4-yl)-piperazine

The compound can be prepared from 4-Nitro-2-trifluoromethyl-pyridine1-oxide [147149-97-1] in analogy to the procedure used for thepreparation of 4-Bromo-2-methyl-6-trifluoromethyl-pyridine [615579-78-1](WO03087056). MS (m/e): 227 (M+H⁺, 100%)

EXAMPLE 5.18 Preparation of 1-(6-Methyl-pyridin-3-yl)-piperazine

The compound was prepared in analogy to compound 1.1 from5-Bromo-2-methyl-pyridine (commercial). MS (m/e): 178.1 (M+H⁺, 100%)

In analogy to Example 5 compounds 363 to 461 of the following table wereprepared from the acid derivatives and piperazine derivatives:

Expl. MW found No. Systematic Name Starting materials (MH⁺) 3632-[4-(2-Isopropoxy-5- 2-Piperazin-1-yl-5- 496.3 methanesulfonyl-trifluoromethyl-benzonitrile benzoyl)-piperazin-1- (compound 5.2) and 2-yl]-5-trifluoromethyl- Isopropoxy-5-methanesulfonyl- benzonitrilebenzoic acid (compound 1.2) 364 4-[4-(2-Isopropoxy-5-4-Piperazin-1-yl-2- 496.3 methanesulfonyl- trifluoromethyl-benzonitrilebenzoyl)-piperazin-1- (WO0017163) and 2- yl]-2-trifluoromethyl-Isopropoxy-5-methanesulfonyl- benzonitrile benzoic acid (compound 1.2)365 1-{4-[4-(2-Isopropoxy- 1-(4-Piperazin-1-yl-2- 513.45-methanesulfonyl- trifluoromethyl-phenyl)- benzoyl)-piperazin-1-ethanone (WO0210277) and yl]-2-trifluoromethyl-2-Isopropoxy-5-methanesulfonyl- phenyl}-ethanone benzoic acid (compound1.2) 366 2-Chloro-4-[4-(2- 2-Chloro-4-piperazin-1-yl- 462.3isopropoxy-5- benzonitrile (compound 5.8) methanesulfonyl- and2-Isopropoxy-5- benzoyl)-piperazin-1- methanesulfonyl-benzoic acidyl]-benzonitrile (compound 1.2) 367 1-{2-Fluoro-4-[4-(2-1-(2-Fluoro-4-piperazin-1-yl- 463.4 isopropoxy-5- phenyl)-ethanone(compound methanesulfonyl- 5.9) and 2-Isopropoxy-5-benzoyl)-piperazin-1- methanesulfonyl-benzoic acid yl]-phenyl}-ethanone(compound 1.2) 368 [4-(3-Fluoro-4- 1-(3-Fluoro-4- 499.3 methanesulfonyl-methanesulfonyl-phenyl)- phenyl)-piperazin-1- piperazine (compound 5.10)yl]-(2-isopropoxy-5- and 2-Isopropoxy-5- methanesulfonyl-methanesulfonyl-benzoic acid phenyl)-methanone (compound 1.2) 3691-{4-[4-(2-Cyclopropyl 1-(2-Fluoro-4-piperazin-1-yl- 475.4methoxy-5-methanesulfonyl- phenyl)-ethanone (compoundbenzoyl)-piperazin-1-yl]-2- 5.9) and 2-Cyclopropylfluoro-phenyl}-ethanone methoxy-5-methanesulfonyl- benzoic acid(compound 1.4) 370 (2-Cyclopropyl 1-(3-Fluoro-4-methanesulfonyl- 511.4methoxy-5-methanesulfonyl- phenyl)-piperazine phenyl)-[4-(3-fluoro-4-(compound 5.10) and 2- methanesulfonyl-phenyl)- Cyclopropylmethoxy-5-piperazin-1-yl]methanone- methanesulfonyl-benzoic acid (compound 1.4)371 [4-(3-Fluoro-4- 1-(3-Fluoro-4-methanesulfonyl- 513.4methanesulfonyl- phenyl)-piperazine phenyl)-piperazin-1- (compound 5.10)and 2- yl]-(2-isobutoxy-5- Isobutoxy-5-methanesulfonyl- methanesulfonyl-benzoic acid (compound 1.3) phenyl)-methanone 372 1-{2-Fluoro-4-[4-(2-1-(2-Fluoro-4-piperazin-1-yl- 477.3 isobutoxy-5- phenyl)-ethanone(compound methanesulfonyl- 5.9) and 2-Isobutoxy-5- benzoyl)-piperazin-1-methanesulfonyl-benzoic acid yl]-phenyl}-ethanone (compound 1.3) 3732-[4-(2- 2-Piperazin-1-yl-5- 522.4 Cyclopentyloxy-5-trifluoromethyl-benzonitrile methanesulfonyl- (compound 5.2) and 2-benzoyl)-piperazin-1- Cyclopentyloxy-5-methanesulfonyl-yl]-5-trifluoromethyl- benzoic acid (compound 1.6) benzonitrile 3742-[4-(2-Cyclopropyl 2-Piperazin-1-yl-5-trifluoromethyl- 508.6methoxy-5-methanesulfonyl- benzonitrile (compound 5.2) and 2-benzoyl)-piperazin-1-yl]-5- Cyclopropylmethoxy-5- trifluoromethyl-methanesulfonyl-benzoic acid benzonitrile (compound 1.4) 3752-[4-(2-Isobutoxy-5- 2-Piperazin-1-yl-5-trifluoromethyl- 510.6methanesulfonyl- benzonitrile (compound 5.2) and 2-benzoyl)-piperazin-1- Isobutoxy-5-methanesulfonyl-yl]-5-trifluoromethyl- benzoic acid (compound 1.3) benzonitrile 3762-{4-[5-Methanesulfonyl- 2-Piperazin-1-yl-5-trifluoromethyl- 536.52-(2,2,2- benzonitrile trifluoro-ethoxy)- (compound 5.2) and 5-benzoyl]-piperazin-1- Methanesulfonyl-2-(2,2,2- yl}-5-trifluoromethyl-trifluoro-ethoxy)-benzoic acid benzonitrile (compound 1.5) 377rac-[4-(3-Fluoro-4- 1-(3-Fluoro-4-methanesulfonyl- 553.2methanesulfonyl- phenyl)-piperazine phenyl)-piperazin-1- (compound 5.10)and rac-5- yl]-[5-methanesulfonyl- Methanesulfonyl-2-(2,2,2-2-(2,2,2-trifluoro-1- trifluoro-1-methyl-ethoxy)- methyl-ethoxy)-benzoic acid (compound 3.1) phenyl]-methanone 378 rac-1-(2-Fluoro-4-{4-1-(2-Fluoro-4-piperazin-1-yl- 517.4 [5-methanesulfonyl-2-phenyl)-ethanone (compound (2,2,2-trifluoro-1- 5.9) andrac-5-Methanesulfonyl- methyl-ethoxy)- 2-(2,2,2-trifluoro-1-benzoyl]-piperazin-1- methyl-ethoxy)-benzoic acid yl}-phenyl)-ethanone(compound 3.1) 379 1-{4-Fluoro-2-[4-(2- 1-(4-Fluoro-2-piperazin-1 yl-463.4 isopropoxy-5- phenyl)-ethanone (compound methanesulfonyl- 5.11)and 2-Isopropoxy-5- benzoyl)-piperazin-1- methanesulfonyl-benzoic acidyl]-phenyl}-ethanone (compound 1.2) 380 3-[4-(2-Fluoro-4-1-(2-Fluoro-4-trifluoromethyl- 454.6 trifluoromethyl- phenyl)-piperazine(compound phenyl)-piperazine-1- 1.1) and 6-Isopropoxy- carbonyl]-4-isophthalamic acid (compound 5.12) isopropoxy-benzamide 3814-Isopropoxy-3-[4-(4- 1-(4-Trifluoromethyl-phenyl)- 436.4trifluoromethyl- piperazine (commercial) and phenyl)-piperazine-1-6-Isopropoxy-isophthalamic carbonyl]-benzamide acid (compound 5.12) 3823-[4-(3-Fluoro-4- 1-(3-Fluoro-4-trifluoromethyl- 454.6 trifluoromethyl-phenyl)-piperazine (compound phenyl)-piperazine-1- 5.1) and6-Isopropoxy- carbonyl]-4- isophthalamic acid (compound 5.12)isopropoxy-benzamide 383 3-[4-(2-Fluoro-4-1-(2-Fluoro-4-methanesulfonyl- 464.4 methanesulfonyl- phenyl)-piperazinephenyl)-piperazine-1- (commercial) and 6- carbonyl]-4-Isopropoxy-isophthalamic acid isopropoxy-benzamide (compound 5.12) 3843-[4-(2-Cyano-4- 2-Piperazin-1-yl-5-trifluoromethyl- 461.4trifluoromethyl- benzonitrile phenyl)-piperazine-1- (compound 5.2) and6- carbonyl]-4- Isopropoxy-isophthalamic acid isopropoxy-benzamide(compound 5.12) 385 3-[4-(4-Cyano-phenyl)- 4-Piperazin-1-yl-benzonitrile393.2 piperazine-1-carbonyl]- (commercial) and 6- 4-isopropoxy-benzamideIsopropoxy-isophthalamic acid (compound 5.12) 386 3-[4-(4-Cyano-2-3-Fluoro-4-piperazin-1-yl- 411.4 fluoro-phenyl)- benzonitrile(WO9625414) and piperazine-1-carbonyl]- 6-Isopropoxy-isophthalamic4-isopropoxy-benzamide acid (compound 5.12) 387 3-[4-(4-Cyano-3-2-Fluoro-4-piperazin-1-yl- 411.4 fluoro-phenyl)- benzonitrile (WO9808835) piperazine-1-carbonyl]- and 6-Isopropoxy-4-isopropoxy-benzamide isophthalamic acid (compound 5.12) 3883-[4-(4-Acetyl-2- 1-(3-Fluoro-4-piperazin-1-yl- 428.6 fluoro-phenyl)-phenyl)-ethanone piperazine-1-carbonyl]- (WO9714690) and 6-4-isopropoxy- Isopropoxy-isophthalamic acid benzamide (compound 5.12)389 [4-(2,3-Difluoro-4- 1-(2,3-Difluoro-4- 517.4 methanesulfonyl-methanesulfonyl-phenyl)- phenyl)-piperazin-1- piperazine (compound 5.3)yl]-(2-isopropoxy-5- and 2-Isopropoxy-5- methanesulfonyl-methanesulfonyl-benzoic acid phenyl)-methanone (compound 1.2) 390(5-Ethanesulfonyl-2- 1-(4-Trifluoromethyl-phenyl)- 485.5isopropoxy-phenyl)-[4- piperazine (commercial) and (4-trifluoromethyl-5-Ethanesulfonyl-2- phenyl)-piperazin-1- isopropoxy-benzoic acidyl]-methanone (compound 5.13) 391 (5-Ethanesulfonyl-2- 1-(2-Fluoro-4-513.4 isopropoxy-phenyl)-[4- methanesulfonyl-phenyl)- (2-fluoro-4-piperazine (commercial) and methanesulfonyl- 5-Ethanesulfonyl-2-phenyl)-piperazin-1- isopropoxy-benzoic acid yl]-methanone (compound5.13) 392 4-[4-(5-Ethanesulfonyl- 3-Fluoro-4-piperazin-1-yl- 460.52-isopropoxy-benzoyl)- benzonitrile (WO9625414) and piperazin-1-yl]-3-5-Ethanesulfonyl-2- fluoro-benzonitrile isopropoxy-benzoic acid(compound 5.13) 393 (5-Ethanesulfonyl-2- 1-(2-Fluoro-4-trifluoromethyl-503.3 isopropoxy-phenyl)-[4- phenyl)-piperazine (compound (2-fluoro-4-1.1) and 5-Ethanesulfonyl-2- trifluoromethyl- isopropoxy-benzoic acidphenyl)-piperazin-1- (compound 5.13) yl]-methanone 394[4-(2,3-Difluoro-4- 1-(2,3-Difluoro-4- 531.3 methanesulfonyl-methanesulfonyl-phenyl)- phenyl)-piperazin-1- piperazine (compound 5.3)yl]-(5-ethanesulfonyl-2- and 5-Ethanesulfonyl-2- isopropoxy-phenyl)-isopropoxy-benzoic acid methanone (compound 5.13) 395(2-Cyclopentyloxy-5- 1-(2,3-Difluoro-4- 542.1 methanesulfonyl-methanesulfonyl-phenyl)- phenyl)-[4-(2,3- piperazine (compound 5.3)difluoro-4- and 2-Cyclopentyloxy-5- methanesulfonyl- methanesulfonyl-phenyl)-piperazin-1- benzoic acid (compound 1.6) yl]-methanone 396(2-Cyclopropylmethoxy- 1-(2,3-Difluoro-4- 529.3 5-methanesulfonyl-methanesulfonyl-phenyl)- phenyl)-[4-(2,3-difluoro- piperazine (compound5.3) 4-methanesulfonyl- and 2-Cyclopropylmethoxy-5- phenyl)-piperazin-1-methanesulfonyl-benzoic acid yl]-methanone (compound 1.4) 397[4-(2,3-Difluoro-4- 1-(2,3-Difluoro-4- 557.2 methanesulfonyl-methanesulfonyl-phenyl)- phenyl)-piperazin-1- piperazine (compound 5.3)yl]-[5-methanesulfonyl- and 5-Methanesulfonyl-2- 2-(2,2,2-trifluoro-(2,2,2-trifluoro-ethoxy)- ethoxy)-phenyl]- benzoic acid (compound 1.5)methanone 398 rac-[4-(2,3-Difluoro-4- 1-(2,3-Difluoro-4- 571.3methanesulfonyl- methanesulfonyl-phenyl)- phenyl)-piperazin-1-piperazine (compound 5.3) yl]-[5-methanesulfonyl- andrac-5-Methanesulfonyl-2- 2-(2,2,2-trifluoro-1-(2,2,2-trifluoro-1-methyl- methyl-ethoxy)- ethoxy)-benzoic acidphenyl]-methanone (compound 3.1) 399 [4-(2,3-Difluoro-4-1-(2,3-Difluoro-4- 543.2 methanesulfonyl- methanesulfonyl-phenyl)-phenyl)-piperazin-1- piperazine (compound 5.3) yl]-(5-methanesulfonyl-and 5-Methanesulfonyl-2- 2-trifluoromethoxy- trifluoromethoxy-benzoicacid phenyl)-methanone (compound 2.15) 400 [4-(4-Difluoromethyl-1-(4-Difluoromethyl-2-fluoro- 471.1 2-fluoro-phenyl)- phenyl)-piperazine(compound piperazin-1-yl]-(2- 5.14) and 2-Isopropoxy-5- isopropoxy-5-methanesulfonyl-benzoic acid methanesulfonyl- (compound 1.2)phenyl)-methanone 401 [4-(3-Chloro-5- 1-(3-Chloro-5-trifluoromethyl-546.3 trifluoromethyl- pyridin-2-yl)- pyridin-2-yl)-piperazin-piperazine (commercial) and 1-yl]-[5-methanesulfonyl-5-Methanesulfonyl-2-(2,2,2- 2-(2,2,2-trifluoro-ethoxy)-trifluoro-ethoxy)-benzoic acid phenyl]-methanone (compound 1.5) 402[5-Methanesulfonyl-2- 1-(5-Trifluoromethyl-pyridin- 512.4(2,2,2-trifluoro- 2-yl)-piperazine (commercial) ethoxy)-phenyl]-[4-(5-and 5-Methanesulfonyl-2- trifluoromethyl- (2,2,2-trifluoro-ethoxy)-pyridin-2-yl)-piperazin- benzoic acid (compound 1.5) 1-yl]-methanone 4036-{4-[5-Methanesulfonyl- 6-Piperazin-1-yl-nicotinonitrile 469.32-(2,2,2-trifluoro-ethoxy)- (commercial) and 5- benzoyl]-piperazin-1-Methanesulfonyl-2-(2,2,2- yl}-nicotinonitrile trifluoro-ethoxy)-benzoicacid (compound 1.5) 404 6-[4-(2-Cyclopropylmethoxy-6-Piperazin-1-yl-nicotinonitrile 441.4 5-methanesulfonyl-benzoyl)-(commercial) and 2- piperazin-1-yl]-nicotinonitrileCyclopropylmethoxy-5- methanesulfonyl-benzoic acid (compound 1.4) 405(2-Cyclopropylmethoxy-5- 1-(5-Trifluoromethyl-pyridin- 484.5methanesulfonyl- 2-yl)-piperazine (commercial)phenyl)-[4-(5-trifluoromethyl- and 2-Cyclopropylmethoxy-5-pyridin-2-yl)-piperazin- methanesulfonyl-benzoic acid 1-yl]-methanone(compound 1.4) 406 [4-(3-Chloro-5- 1-(3-Chloro-5-trifluoromethyl- 518.3trifluoromethyl- pyridin-2-yl)- pyridin-2-yl)-piperazin- piperazine(commercial) and 1-yl]-(2-cyclopropylmethoxy- 2-Cyclopropylmethoxy-5-5-methanesulfonyl- methanesulfonyl-benzoic acid phenyl)-methanone(compound 1.4) 407 rac-[4-(3-Chloro-5- 1-(3-Chloro-5-trifluoromethyl-560.3 trifluoromethyl- pyridin-2-yl)- pyridin-2-yl)-piperazin-piperazine (commercial) and 1-yl]-[5-methanesulfonyl-rac-5-Methanesulfonyl-2- 2-(2,2,2- (2,2,2-trifluoro-1-methyl-trifluoro-1-methyl- ethoxy)-benzoic acid ethoxy)-phenyl]- (compound 3.1)methanone 408 rac-[5-Methanesulfonyl- 1-(5-Trifluoromethyl-pyridin-526.2 2-(2,2,2- 2-yl)-piperazine (commercial) trifluoro-1-methyl- andrac-5-Methanesulfonyl-2- ethoxy)-phenyl]-[4-(5-(2,2,2-trifluoro-1-methyl- trifluoromethyl- ethoxy)-benzoic acidpyridin-2-yl)-piperazin- (compound 3.1) 1-yl]-methanone 409 rac-6-{4-[5-6-Piperazin-1-yl-nicotinonitrile 483.4 Methanesulfonyl-2- (commercial)and rac-5- (2,2,2-trifluoro-1- Methanesulfonyl-2-(2,2,2- methyl-ethoxy)-trifluoro-1-methyl-ethoxy)- benzoyl]-piperazin-1- benzoic acid (compound3.1) yl}-nicotinonitrile 410 [4-(6-Chloro-5-1-(6-Chloro-5-trifluoromethyl- 518.3 trifluoromethyl- pyridin-2-yl)-pyridin-2-yl)-piperazin- piperazine (WO03097636) and1-yl]-(2-cyclopropyl 2-Cyclopropylmethoxy-5- methoxy-5-methanesulfonyl-methanesulfonyl-benzoic acid phenyl)-methanone (compound 1.4) 4116-[4-(2- 6-Piperazin-1-yl-nicotino 455.5 Cyclopentyloxy-5- nitrile(commercial) and 2- methanesulfonyl- Cyclopentyloxy-5-methanesulfonyl-benzoyl)-piperazin-1- benzoic acid (compound 1.6) yl]-nicotinonitrile412 (2-Cyclopentyloxy-5- 1-(5-Trifluoromethyl-pyridin- 498.3methanesulfonyl- 2-yl)-piperazine (commercial) phenyl)-[4-(5- and2-Cyclopentyloxy-5- trifluoromethyl methanesulfonyl-benzoic acidpyridin-2-yl)-piperazin- (compound 1.6) 1-yl]-methanone 413[4-(3-Chloro-5- 1-(3-Chloro-5-trifluoromethyl- 532.3 trifluoromethyl-pyridin-2-yl)- pyridin-2-yl)-piperazin- piperazine (commercial) and1-yl]-(2- 2-Cyclopentyloxy-5- cyclopentyloxy-5- methanesulfonyl-benzoicacid methanesulfonyl- (compound 1.6) phenyl)-methanone 414[4-(6-Chloro-5- 1-(6-Chloro-5-trifluoromethyl- 506.3 trifluoromethyl-pyridin-2-yl)- pyridin-2-yl)-piperazin- piperazine (WO03097636) and1-yl]-(2-isopropoxy-5- 2-Isopropoxy-5-methanesulfonyl- methanesulfonyl-benzoic acid (compound 1.2) phenyl)-methanone 415 (2-Isopropoxy-5-1-(5-Trifluoromethyl-pyridin- 472.2 methanesulfonyl- 2-yl)-piperazine(commercial) phenyl)-[4-(5- and 2-Isopropoxy-5-methanesulfonyl-trifluoromethyl- benzoic acid (compound 1.2) pyridin-2-yl)-piperazin-1-yl]-methanone 416 6-[4-(2-Isopropoxy-5-6-Piperazin-1-yl-nicotinonitrile 429.5 methanesulfonyl- (commercial) and2- benzoyl)-piperazin-1- Isopropoxy-5-methanesulfonyl-yl]-nicotinonitrile benzoic acid (compound 1.2) 417 [4-(3-Chloro-5-1-(3-Chloro-5-trifluoromethyl- 506.3 trifluoromethyl- pyridin-2-yl)-pyridin-2-yl)-piperazin- piperazine (commercial) and1-yl]-(2-isopropoxy-5- 2-Isopropoxy-5-methanesulfonyl- methanesulfonyl-benzoic acid (compound 1.2) phenyl)-methanone 418 rac-[4-(5-Chloro-1-(5-Chloro-pyridin-2-yl)- 492.3 pyridin-2-yl)-piperazin- piperazine(WO01062751) and 1-yl]-[5-methanesulfonyl- rac-5-Methanesulfonyl-2-2-(2,2,2-trifluoro-1-methyl- (2,2,2-trifluoro-1-methyl- ethoxy)-phenyl]-ethoxy)-benzoic acid methanone (compound 3.1) 419 [4-(5-Chloro-pyridin-1-(5-Chloro-pyridin-2-yl)- 464.3 2-yl)-piperazin-1-yl]- piperazine(WO01062751) and (2-cyclopentyloxy-5- 2-Cyclopentyloxy-5-methanesulfonyl- methanesulfonyl-benzoic acid phenyl)-methanone(compound 1.6) 420 [4-(5-Chloro-pyridin- 1-(5-Chloro-pyridin-2-yl)-450.4 2-yl)-piperazin-1-yl]- piperazine (WO01062751) and(2-cyclopropylmethoxy- 2-Cyclopropylmethoxy-5- 5-methanesulfonyl-methanesulfonyl-benzoic acid phenyl)-methanone (compound 1.4) 421[4-(5-Chloro-pyridin- 1-(5-Chloro-pyridin-2-yl)- 478.22-yl)-piperazin-1-yl]- piperazine (WO01062751) and [5-methanesulfonyl-2-5-Methanesulfonyl-2-(2,2,2- (2,2,2-trifluoro- trifluoro-ethoxy)-benzoicacid ethoxy)-phenyl]- (compound 1.5) methanone 422 [4-(5-Chloro-pyridin-1-(5-Chloro-pyridin-2-yl)- 438.3 2-yl)-piperazin-1-yl]- piperazine(WO01062751) and (2-isopropoxy-5- 2-Isopropoxy-5-methanesulfonyl-methanesulfonyl- benzoic acid (compound 1.2) phenyl)-methanone 423Rac-[4-(6-Chloro- 3-Chloro-6-piperazin-1-yl- 493.3 pyridazin-3-yl)-pyridazine (WO02030405) and piperazin-1-yl]-[5- rac-5-Methanesulfonyl-2-methanesulfonyl-2- (2,2,2-trifluoro-1-methyl- (2,2,2-trifluoro-1-ethoxy)-benzoic acid methyl-ethoxy)- (compound 3.1) phenyl]-methanone424 [4-(6-Chloro- 3-Chloro-6-piperazin-1-yl- 465.4 pyridazin-3-yl)-pyridazine (WO02030405) and piperazin-1-yl]-(2- 2-Cyclopentyloxy-5-cyclopentyloxy-5- methanesulfonyl-benzoic acid methanesulfonyl-(compound 1.6) phenyl)-methanone 425 (2-Isopropoxy-5-1-(6-Trifluoromethyl-pyridin- 472.2 methanesulfonyl- 3-yl)-piperazine(compound phenyl)-[4-(6- 5.15) and 2-Isopropoxy-5- trifluoromethyl-methanesulfonyl-benzoic acid pyridin-3-yl)-piperazin- (compound 1.2)1-yl]-methanone 426 [5-Methanesulfonyl-2- 1-(6-Trifluoromethyl-pyridin-512.4 (2,2,2-trifluoro- 3-yl)-piperazine (compoundethoxy)-phenyl]-[4-(6- 5.15) and 5-Methanesulfonyl- trifluoromethyl-2-(2,2,2-trifluoro-ethoxy)- pyridin-3-yl)-piperazin- benzoic acid(compound 1.5) 1-yl]-methanone 427 rac-[5-Methanesulfonyl-1-(6-Trifluoromethyl-pyridin- 526.2 2-(2,2,2- 3-yl)-piperazine (compoundtrifluoro-1-methyl- 5.15) and rac-5-Methanesulfonyl-ethoxy)-phenyl]-[4-(6- 2-(2,2,2-trifluoro-1- trifluoromethyl-methyl-ethoxy)-benzoic acid pyridin-3-yl)-piperazin- (compound 3.1)1-yl]-methanone 428 3-Fluoro-4-[4-(2- 3-Fluoro-4-piperazin-1-yl- 493.4isopropoxy-5-methanesulfonyl- benzoic acid ethyl esterbenzoyl)-piperazin-1-yl]- (compound 5.16) and 2- benzoic acid ethylester Isopropoxy-5-methanesulfonyl- benzoic acid (compound 1.2) 429[4-(5-Bromo-pyridin- 1-(5-Bromo-pyridin-2-yl)- 482.42-yl)-piperazin-1-yl]- piperazine (WO9534555) and (2-isopropoxy-5-2-Isopropoxy-5-methanesulfonyl- methanesulfonyl- benzoic acid (compound1.2) phenyl)-methanone 430 (2-Cyclopentyloxy-5-1-(6-Trifluoromethyl-pyridin- 498.3 methanesulfonyl- 3-yl)-piperazine(compound phenyl)-[4-(6-trifluoromethyl- 5.15) and 2-Cyclopentyloxy-5-pyridin-3-yl)- methanesulfonyl-benzoic acid piperazin-1-yl]- (compound1.6) methanone 431 (2-Cyclopropyl 1-(6-Trifluoromethyl-pyridin- 484.5methoxy-5-methanesulfonyl- 3-yl)-piperazine (compound phenyl)-[4-(6-5.15) and 2-Cyclopropyl trifluoromethyl- methoxy-5-methanesulfonyl-pyridin-3-yl)-piperazin- benzoic acid (compound 1.4) 1-yl]-methanone 432[4-(5-Bromo-pyridin- 1-(5-Bromo-pyridin-2-yl)- 522.22-yl)-piperazin-1-yl]- piperazine (WO 9534555) and [5-methanesulfonyl-2-5-Methanesulfonyl-2-(2,2,2- (2,2,2-trifluoro- trifluoro-ethoxy)-benzoicacid ethoxy)-phenyl]- (compound 1.5) methanone 433 [5-Methanesulfonyl-2-1-(2-Trifluoromethyl-pyridin- 512.4 (2,2,2-trifluoro- 4-yl)-piperazine(compound ethoxy)-phenyl]-[4-(2- 5.17) and 5-Methanesulfonyl-trifluoromethyl- 2-(2,2,2-trifluoro-ethoxy)- pyridin-4-yl)-piperazin-benzoic acid (compound 1.5) 1-yl]-methanone 434 (2-Isopropoxy-5-1-(2-Trifluoromethyl-pyridin- 472.2 methanesulfonyl- 4-yl)-piperazine(compound phenyl)-[4-(2- 5.17) and 2-Isopropoxy-5- trifluoromethyl-methanesulfonyl-benzoic acid pyridin-4-yl)-piperazin- (compound 1.2)1-yl]-methanone 435 rac-[4-(5-Bromo- 1-(5-Bromo-pyridin-2-yl)- 536.3pyridin-2-yl)-piperazin- piperazine (WO 9534555) and1-yl]-[5-methanesulfonyl- rac-5-Methanesulfonyl-2- 2-(2,2,2-(2,2,2-trifluoro-1-methyl- trifluoro-1-methyl- ethoxy)-benzoic acidethoxy)-phenyl]- (compound 3.1) methanone 436 [4-(3-Fluoro-5-1-(3-Fluoro-5-trifluoromethyl- 530.3 trifluoromethyl-pyridin-2-yl)-piperazine pyridin-2-yl)-piperazin- (compound 5.5) and 5-1-yl]-[5-methanesulfonyl- Methanesulfonyl-2-(2,2,2- 2-(2,2,2-trifluoro-ethoxy)-benzoic acid trifluoro-ethoxy)- (compound 1.5)phenyl]-methanone 437 [4-(3-Fluoro-5- 1-(3-Fluoro-5-trifluoromethyl-490.4 trifluoromethyl- pyridin-2-yl)-piperazine pyridin-2-yl)-piperazin-(compound 5.5) and 2- 1-yl]-(2-isopropoxy-5-Isopropoxy-5-methanesulfonyl- methanesulfonyl- benzoic acid (compound1.2) phenyl)-methanone 438 rac-[4-(3-Fluoro-5-1-(3-Fluoro-5-trifluoromethyl- 544.3 trifluoromethyl-pyridin-2-yl)-piperazine pyridin-2-yl)-piperazin- (compound 5.5) andrac-5- 1-yl]-[5-methanesulfonyl- Methanesulfonyl-2-(2,2,2-2-(2,2,2-trifluoro- trifluoro-1-methyl-ethoxy)- 1-methyl-ethoxy)-benzoic acid (compound 3.1) phenyl]-methanone 439 (2-Cyclopentyloxy-5-1-(3-Fluoro-5-trifluoromethyl- 516.4 methanesulfonyl-pyridin-2-yl)-piperazine phenyl)-[4-(3-fluoro-5- (compound 5.5) and 2-trifluoromethyl- Cyclopentyloxy-5-methanesulfonyl-pyridin-2-yl)-piperazin- benzoic acid (compound 1.6) 1-yl]-methanone 440(2-Cyclopropylmethoxy- 1-(3-Fluoro-5-trifluoromethyl- 502.35-methanesulfonyl- pyridin-2-yl)-piperazine phenyl)-[4-(3-fluoro-5-(compound 5.5) and 2- trifluoromethyl- Cyclopropylmethoxy-5-pyridin-2-yl)-piperazin- methanesulfonyl-benzoic acid 1-yl]-methanone(compound 1.4) 441 rac-[5-Methanesulfonyl- 1-(2-Trifluoromethyl-pyridin-526.2 2-(2,2,2- 4-yl)-piperazine (compound trifluoro-1-methyl- 5.17) andrac-5-Methanesulfonyl- ethoxy)-phenyl]-[4-(2- 2-(2,2,2-trifluoro-1-trifluoromethyl- methyl-ethoxy)-benzoic acid pyridin-4-yl)-piperazin-(compound 3.1) 1-yl]-methanone 442 [5-Methanesulfonyl-2-1-(6-Methyl-pyridin-3-yl)- 458.4 (2,2,2-trifluoro- piperazine (compound5.18) ethoxy)-phenyl]-[4-(6- and 5-Methanesulfonyl-2-methyl-pyridin-3-yl)- (2,2,2-trifluoro-ethoxy)- piperazin-1-yl]- benzoicacid (compound 1.5) methanone 443 (2-Isopropoxy-5-1-(6-Methyl-pyridin-3-yl)- 418.3 methanesulfonyl- piperazine (compound5.18) phenyl)-[4-(6-methyl- and 2-Isopropoxy-5- pyridin-3-yl)-piperazin-methanesulfonyl-benzoic acid 1-yl]-methanone (compound 1.2) 444(2-Cyclopentyloxy-5- 1-(6-Methyl-pyridin-3-yl)- 444.4 methanesulfonyl-piperazine (compound 5.18) phenyl)-[4-(6-methyl- and 2-Cyclopentyloxy-5-pyridin-3-yl)-piperazin- methanesulfonyl-benzoic acid 1-yl]-methanone(compound 1.6) 445 (2-Cyclopropyl 1-(6-Methyl-pyridin-3-yl)- 430.5methoxy-5-methanesulfonyl- piperazine (compound 5.18) phenyl)-[4-(6- and2-Cyclopropylmethoxy-5- methyl-pyridin-3-yl)- methanesulfonyl-benzoicacid piperazin-1-yl]-methanone (compound 1.4) 446 [5-Methanesulfonyl-2-1-(5-Methyl-pyridin-2-yl)- 458.0 (2,2,2-trifluoro- piperazine(WO03032996) and ethoxy)-phenyl]-[4-(5- 5-Methanesulfonyl-2-(2,2,2-methyl-pyridin-2-yl)- trifluoro-ethoxy)-benzoic acidpiperazin-1-yl]-methanone (compound 1.5) 447 (2-Isopropoxy-5-1-(5-Methyl-pyridin-2-yl)- 418.3 methanesulfonyl- piperazine(WO03032996) and phenyl)-[4-(5-methyl- 2-Isopropoxy-5-methanesulfonyl-pyridin-2-yl)-piperazin- benzoic acid (compound 1.2) 1-yl]-methanone 448(2-Cyclopropylmethoxy- 1-(5-Methyl-pyridin-2-yl)- 430.55-methanesulfonyl- piperazine (WO03032996) and phenyl)-[4-(5-2-Cyclopropylmethoxy-5- methyl-pyridin-2-yl)- methanesulfonyl-benzoicacid piperazin-1-yl]-methanone (compound 1.4) 449rac-[5-Methanesulfonyl- 1-(5-Methyl-pyridin-2-yl- 472.3 2-(2,2,2-piperazine (WO03032996) and trifluoro-1-methyl- rac-5-Methanesulfonyl-2-ethoxy)-phenyl]-[4-(5- (2,2,2-trifluoro-1-methyl- methyl-pyridin-2-yl)-ethoxy)-benzoic acid piperazin-1-yl]-methanone (compound 3.1) 450rac-[5-Methanesulfonyl- 1-(6-Methyl-pyridin-3-yl)- 472.2 2-(2,2,2-piperazine (compound 5.18) trifluoro-1-methyl- andrac-5-Methanesulfonyl-2- ethoxy)-phenyl]-[4-(6-(2,2,2-trifluoro-1-methyl- methyl-pyridin-3-yl)- ethoxy)-benzoic acidpiperazin-1-yl]-methanone (compound 3.1) 451 [5-Methanesulfonyl-2-1-(4-Trifluoromethyl-pyridin- 512.4 (2,2,2-trifluoro- 2-yl)-piperazineethoxy)-phenyl]-[4-(4- (WO02002529) and 5- trifluoromethyl-Methanesulfonyl-2-(2,2,2- pyridin-2-yl)-piperazin-trifluoro-ethoxy)-benzoic acid 1-yl]-methanone (compound 1.5) 452(2-Isopropoxy-5- 1-(4-Trifluoromethyl-pyridin- 472.3 methanesulfonyl-2-yl)-piperazine phenyl)-[4-(4- (WO02002529) and 2- trifluoromethyl-Isopropoxy-5-methanesulfonyl- pyridin-2-yl)-piperazin- benzoic acid(compound 1.2) 1-yl]-methanone 453 (2-tert-Butoxy-5-1-(4-Trifluoromethyl-pyridin- 486.2 methanesulfonyl- 2-yl)-piperazinephenyl)-[4-(4- (WO02002529) and 2-tert- trifluoromethyl-Butoxy-5-methanesulfonyl- pyridin-2-yl)-piperazin- benzoic acid(compound 2.19) 1-yl]-methanone 454 [4-(2-Fluoro-4-1-(2-Fluoro-4-methane 570.4 methanesulfonyl- sulfonyl-phenyl)-piperazine(M + NH₄ ⁺) phenyl)-piperazin-1- (commercial) and 5-Methaneyl]-[5-methanesulfonyl- sulfonyl-2-((S)-2,2,2-trifluoro-2-((S)-2,2,2-trifluoro-1- 1-methyl-ethoxy)-benzoic acid methyl-ethoxy)-(compound 5.6) phenyl]-methanone 455 rac-[5-Methanesulfonyl-1-(4-Trifluoromethyl-pyridin- 526.0 2-(2,2,2- 2-yl)-piperazinetrifluoro-1-methyl- (WO02002529) and rac-5- ethoxy)-phenyl]-[4-(4-Methanesulfonyl-2-(2,2,2- trifluoromethyl- trifluoro-1-methyl-ethoxy)-pyridin-2-yl)-piperazin- benzoic acid (compound 3.1) 1-yl]-methanone 456[4-(2-Fluoro-4- 1-(2-Fluoro-4- 570.4 methanesulfonyl-methanesulfonyl-phenyl)- (M + NH₄ ⁺) phenyl)-piperazin-1- piperazine(commercial) and yl]-[5-methanesulfonyl- 5-Methanesulfonyl-2-((R)-2-((R)-2,2,2-trifluoro- 2,2,2-trifluoro-1-methyl- 1-methyl-ethoxy)-ethoxy)-benzoic acid phenyl]-methanone (compound 5.7) 457(2-Cyclopentyloxy-5- 1-(4-Trifluoromethyl-pyridin- 498.2methanesulfonyl- 2-yl)-piperazine phenyl)-[4-(4- (WO02002529) and 2-trifluoromethyl- Cyclopentyloxy-5- pyridin-2-yl)-piperazin-methanesulfonyl- 1-yl]-methanone benzoic acid (compound 1.6) 458(2-Isopropoxy-5- 1-(6-Trifluoromethyl-pyridin- 472.1methanesulfonyl-phenyl)- 2-yl)-piperazine (EP 462638)[4-(6-trifluoromethyl- and 2-Isopropoxy-5-methanesulfonyl-pyridin-2-yl)-piperazin- benzoic acid (compound 1.2) 1-yl]-methanone 459rac-[5-Methanesulfonyl- 1-(6-Trifluoromethyl-pyridin- 526.0 2-(2,2,2-2-yl)-piperazine (EP 462638) trifluoro-1-methyl- andrac-5-Methanesulfonyl-2- ethoxy)-phenyl]-[4-(6-(2,2,2-trifluoro-1-methyl- trifluoromethyl- ethoxy)-benzoic acidpyridin-2-yl)-piperazin- (compound 3.1) 1-yl]-methanone 460[5-Methanesulfonyl-2- 1-(6-Trifluoromethyl-pyridin- 512.2(2,2,2-trifluoro- 2-yl)-piperazine (EP 462638) ethoxy)-phenyl]-[4-(6-and 5-Methanesulfonyl-2- trifluoromethyl- (2,2,2-trifluoro-ethoxy)-pyridin-2-yl)-piperazin- benzoic acid (compound 1.5) 1-yl]-methanone 4613-Fluoro-4-[4-(2- 1-(4-Difluoromethyl-2-fluoro- 449.1 isopropoxy-5-phenyl)-piperazine (compound methanesulfonyl- 5.14) and 2-Isopropoxy-5-benzoyl)-piperazin-1- methanesulfonyl-benzoic acid yl]-benzaldehyde(compound 1.2)

EXAMPLE 462 Preparation ofrac-{4-[2-Fluoro-4-(1-hydroxy-ethyl)-phenyl]-piperazin-1-yl}-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone

0.086 mmol of1-{3-Fluoro-4-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-phenyl}-ethanonewas dissolved in 1 ml ethanol and 0.26 mmol sodium borohydride was addedThe mixture was refluxed for 40 min., cooled to room temperature,quenched with water, acidified with HCl 1N and extracted with ethylacetate. The combined extracts were dried over Na₂SO₄, filtered and thesolvent was removed in vacuo. The residue was purified on silica elutingwith heptane/ethylacetate to yield after evaporation the title compound.MS (m/e): 465.4 (M+H⁺, 100%)

EXAMPLE 463 Preparation of{4-[2-Fluoro-4-(1-hydroxy-1-methyl-ethyl)-phenyl]-piperazin-1-yl}-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone

To a solution of 0.173 mmol1-{3-Fluoro-4-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-phenyl}-ethanonein tetrahydrofuran (2 ml) was added dropwise 0.190 mmol 1.6MMethyllithium solution in ether at −75° C. The mixture was stirred for 2hours and then allowed to warm to 0° C. The mixture was quenched with a20% NH₄Cl solution and extracted 3 times with ethyl acetate. Thecombined extracts were dried over Na₂SO₄, filtered and the solvent wasremoved in vacuo. The residue was purified on silica, eluting withdichloromethane/MeOH to yield after evaporation the title compound.

MS (m/e): 479.5 (M+H⁺, 100%)

The examples 464-471 have been prepared by separation of the racemicmaterial by chiral HPLC:

Expl. Separation MW found No. Systematic Name Starting materialsConditions (MH⁺) 464 [5-Methanesulfonyl- rac-[5- Chiralpak AD, 525.82-((S or R)-2,2,2- Methanesulfonyl-2- 20% (M) trifluoro-1-methyl-(2,2,2-trifluoro-1- Isopropanol/ ethoxy)-phenyl]-[4- methyl-ethoxy)-Heptane, flow (5-trifluoromethyl- phenyl]-[4-(5- 35 ml, 254 nm,pyridin-2-yl)- trifluoromethyl- 170 min. piperazin-1-yl]- pyridin-2-yl)-methanone piperazin-1-yl]- methanone (example 408) 465[5-Methanesulfonyl- rac-[5-Methanesulfonyl- Chiralpak AD, 525.3 2-((R orS)-2,2,2- 2-(2,2,2- 20% (M) trifluoro-1-methyl- trifluoro-1-methyl-Isopropanol/ ethoxy)-phenyl]-[4- ethoxy)-phenyl]-[4- Heptane, flow(5-trifluoromethyl- (5-trifluoromethyl- 35 ml, 254 nm, pyridin-2-yl)-pyridin-2-yl)- 245 min. piperazin-1-yl]- piperazin-1-yl]- methanonemethanone (example 408) 466 [4-(2-Fluoro-4- rac-[4-(2-Fluoro-4-Chiralpak AD, 543.2 trifluoromethyl- trifluoromethyl- 25%phenyl)-piperazin-1- phenyl)-piperazin-1- Isopropanol/ yl]-[5-yl]-[5-methanesulfonyl- Heptane, flow methanesulfonyl-2- 2-(2,2,2- 35 ml220 nm, ((S or R)-2,2,2- trifluoro-1-methyl- 141 min.trifluoro-1-methyl- ethoxy)-phenyl]- ethoxy)-phenyl]- methanone (examplemethanone 302) 467 [4-(2-Fluoro-4- rac-[4-(2-Fluoro-4- Chiralpak AD,543.2 trifluoromethyl- trifluoromethyl- 25% phenyl)-piperazin-1-phenyl)-piperazin-1- Isopropanol/ yl]-[5- yl]-[5-methanesulfonyl-Heptane, flow methanesulfonyl-2- 2-(2,2,2- 35 ml, 220 nm, ((R orS)-2,2,2- trifluoro-1-methyl- 199 min. trifluoro-1-methyl-ethoxy)-phenyl]- ethoxy)-phenyl]- methanone (example methanone 302) 468[5-Methanesulfonyl- rac-5-Methanesulfonyl- Chiralpak AD, 525.2 2-((S orR)-2,2,2- 2-(2,2,2- 25% trifluoro-1-methyl- trifluoro-1-methyl-Isopropanol/ ethoxy)-phenyl]-[4- ethoxy)-phenyl]-[4- Heptane, flow(4-trifluoromethyl- (4-trifluoromethyl- 35 ml, 220 nm,phenyl)-piperazin-1- phenyl)-piperazin-1- 197 min. yl]-methanoneyl]-methanone (example 301) 469 [5-Methanesulfonyl-rac-5-Methanesulfonyl- Chiralpak AD, 525.2 2-((R or S)-2,2,2- 2-(2,2,2-25% trifluoro-1-methyl- trifluoro-1-methyl- Isopropanol/ethoxy)-phenyl]-[4- ethoxy)-phenyl]-[4- Heptane, flow(4-trifluoromethyl- (4-trifluoromethyl- 35 ml, 220 nm,phenyl)-piperazin-1- phenyl)-piperazin-1- 280 min. yl]-methanoneyl]-methanone (example 301) 470 [4-(3-Fluoro-5- rac-[4-(3-Fluoro-5-Chiralpak AD, 544.3 trifluoromethyl- trifluoromethyl- 20% pyridin-2-yl)-pyridin-2-yl)- Isopropanol/ piperazin-1-yl]-[5- piperazin-1-yl]-[5-Heptane, flow methanesulfonyl-2- methanesulfonyl-2- 35 ml, 254 nm,((S)-2,2,2-trifluoro- (2,2,2-trifluoro-1- 110 min. 1-methyl-ethoxy)-methyl-ethoxy)- phenyl]-methanone phenyl]-methanone (example 438) 471[4-(3-Fluoro-5- rac-[4-(3-Fluoro-5- Chiralpak AD, 544.0 trifluoromethyl-trifluoromethyl- 20% pyridin-2-yl)- pyridin-2-yl)- Isopropanol/piperazin-1-yl]-[5- piperazin-1-yl]-[5- Heptane, flow methanesulfonyl-2-methanesulfonyl-2- 35 ml, 254 nm, ((R)-2,2,2-trifluoro-(2,2,2-trifluoro-1- 145 min. 1-methyl-ethoxy) methyl-ethoxy)-phenyl]-methanone phenyl]-methanone (example 438)

EXAMPLE 6.1 Preparation of 2-isobutoxy-5-methylsulfamoyl-benzoic acid

(a) 5-Chlorosulfonyl-2-hydroxy-benzoic acid

To 3.26 mol chlorosulfonic acid at 0° C. was added 652 mmol salicylicacid in small portions, and the mixture was then allowed to stir at RTfor 1 h, then at 50° C. for 1 h, and finally at 70° C. for 1 h. Themixture was then added dropwise to 1000 ml ice-water with stirring andstirring continued for an additional 30 min. The ensuing white crystalswere collected by filtration, washed three times with water, and thendried in vacuo at 45° C. for 16 h to yield the title compound. MS (m/e):236.8 ([{³⁷Cl}M−H]⁻, 33%), 235.0 ([{³⁷Cl}M−H]⁻, 100%)

(b) 2-Hydroxy-5-methylsulfamoyl-benzoic acid

To 63 mmol 5-chlorosulfonyl-2-hydroxy-benzoic acid in 120 mldichloromethane at RT was added dropwise 317 mmol methylamine (8 Msolution in ethanol), and the mixture was allowed to stir at RT for 1 h.The mixture was then concentrated in vacuo. The residue was suspended in1 M aq NaOH solution and extracted twice with ether. The aqueous phasewas acidified with 5 M aq HCl, saturated with NaCl, and extracted 3times with THF. The combined THF extracts were washed twice withsaturated aqueous NaCl solution and dried with Na₂SO₄. Evaporation invacuo yielded the title compound. MS (m/e): 249.0 (M+NH₄ ⁺, 100%), 231.9(M+H⁺, 63%)

(c) 2-Hydroxy-5-methylsulfamoyl-benzoic acid methyl ester

To 77 mmol 2-hydroxy-5-methylsulfamoyl-benzoic acid in 300 ml THF wasadded 85 mmol CDI, and the mixture heated at 70° C. for 1 h. 770 mmolmethanol was then added, and the mixture was heated at 70° C. for 16 h.The mixture was then cooled to room temperature and concentrated invacuo. The residue was chromatographed on silica gel (eluant: ethylacetate/heptane/dichloromethane 45:45:10) to afford the title compound.MS (m/e): 244.1 ([M−H]⁻, 100%)

(d) 2-Isobutoxy-5-methylsulfamoyl-benzoic acid methyl ester

To 2.9 mmol 2-hydroxy-5-methylsulfamoyl-benzoic acid methyl ester, 3.1mmol 2-methyl-1-propanol and 3.3 mmol triphenylphosphine in 10 ml THFwas added 3.1 mmol di-tert-butyl azodicarboxylate, and the mixture wasstirred at RT for 2 h. The mixture was then concentrated in vacuo. Theresidue was chromatographed on silica gel (eluant: ethyl acetate/heptane2:3) to afford the title compound. MS (m/e): 300.2 ([M−H]⁻, 100%)

(e) 2-Isobutoxy-5-methylsulfamoyl-benzoic acid

To 3.3 mmol 2-isobutoxy-5-methylsulfamoyl-benzoic acid methyl ester in10 ml THF was added 20 mmol 2 M aq NaOH, and the mixture was heated at50° C. for 2 h. The mixture was then cooled to RT and extracted twicewith ether. The aqueous phase was acidified with 10% aq citric acid andextracted 3 times with ethyl acetate. The combined organic phases weredried with Na₂SO₄. Evaporation in vacuo followed by trituration in etherafforded the title compound. MS (m/e): 286.2 ([M−H]⁻, 100%)

In analogy to Example 6.1(d) and (e), compounds 6.2 to 6.10 of thefollowing table were prepared from 2-hydroxy-5-methylsulfamoyl-benzoicacid methyl ester and the appropriate alcohol, followed by hydrolysiswith aqueous sodium hydroxide:

Expl. No Systematic Name alcohol MS (M/e) 6.22-(2,2-Dimethyl-propoxy)-5- 2,2-Dimethyl-1- 300.2methylsulfamoyl-benzoic acid propanol (M − H) 6.3 2-Isopropoxy-5-2-Propanol 272.2 methylsulfamoyl-benzoic acid (M − H) 6.42-Cyclopentyloxy-5- Cyclopentanol 298.2 methylsulfamoyl-benzoic acid (M− H) 6.5 2-Cyclobutoxy-5- Cyclobutanol 284.1 methylsulfamoyl-benzoicacid (M − H) 6.6 2-Cyclopropylmethoxy-5- Cyclopropyl-methanol 284.1methylsulfamoyl-benzoic acid (M − H) 6.7 2-Cyclobutylmethoxy-5-Cyclobutyl-methanol 298.2 methylsulfamoyl-benzoic acid (M − H) 6.85-Methylsulfamoyl-2- Tetrahydro-2H-pyran- 314.1(tetrahydro-pyran-4-yloxy)- 4-ol (M − H) benzoic acid 6.92-(2-Methoxy-ethoxy)-5- 2-Methoxy-ethanol 288.1 methylsulfamoyl-benzoicacid (M − H) 6.10 5-Methylsulfamoyl-2-(3,3,3- 3,3,3-Trifluoro-1- 326.2trifluoro-propoxy)-benzoic propanol (M − H) acid

EXAMPLE 6.11 Preparation of5-methylsulfamoyl-2-(2,2,2-trifluoro-ethoxy)-benzoic acid

(a) 5-Methylsulfamoyl-2-(2,2,2-trifluoro-ethoxy)-benzoic acid methylester

To 3.3 mmol 2-hydroxy-5-methylsulfamoyl-benzoic acid methyl ester and3.3 mmol potassium carbonate in 50 ml acetone was added dropwise 4.9mmol 2,2,2-trifluoro-ethyl trifluoromethanesulfonate, and the mixturewas heated at 60° C. for 16 h. The mixture was then concentrated invacuo. The residue was suspended in dichloromethane and filtered. Thefiltrate was concentrated in vacuo, and the residue was chromatographedon silica gel (eluant: ethyl acetate/heptane 3:7) to afford the tidecompound. MS (m/e): 328.0 (M+H⁺, 100%)

(b) 5-Methylsulfamoyl-2-(2,2,2-trifluoro-ethoxy)-benzoic acid

To 2.3 mmol 5-methylsulfamoyl-2-(2,2,2-trifluoro-ethoxy)-benzoic acidmethyl ester in 10 ml THF was added 20 mmol 2 M aq NaOH, and the mixturewas heated at 50° C. for 2 h. The mixture was then cooled to RT andextracted twice with ether. The aqueous phase was acidified with 10% aqcitric acid and extracted 3 times with ethyl acetate. The combinedorganic phases were dried with Na₂SO₄. Evaporation in vacuo followed bytrituration in ether afforded the tide compound. MS (m/e): 312.0([M−H]⁻, 100%)

EXAMPLE 6.19 Preparation ofrac-5-methylsulfamoyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid

(a) rac-5-Methylsulfamoyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoicacid methyl ester

To 4.1 mmol 2-hydroxy-5-methylsulfamoyl-benzoic acid methyl ester and4.1 mmol potassium carbonate in 5 ml DMF was added dropwise 6.1 mmoltrifluoro-methanesulfonic acid 2,2,2-trifluoro-1-methyl-ethyl ester, andthe mixture was heated at 90° C. for 16 h. The mixture was then cooledto RT, poured onto water and extracted 3 times with ethyl acetate. Thecombined organic phases were dried with Na₂SO₄. Evaporation in vacuofollowed by chromatography on silica gel (eluant: dichloromethane)afforded the title compound.

MS (m/e): 359.2 (M+NH₄ ⁺, 80%), 342.0 (M+H⁺, 100%)

(b) rac-5-Methylsulfamoyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoicacid

To 1.6 mmol5-methylsulfamoyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acidmethyl ester in 10 ml THF was added 20 mmol 2 M aq NaOH, and the mixturewas heated at 50° C. for 2 h. The mixture was then cooled to RT andextracted twice with ether. The aqueous phase was acidified with 10% aqcitric acid and extracted twice with ethyl acetate. The combined organicphases were dried with Na₂SO₄. Evaporation in vacuo followed bytrituration in ether and hexane afforded the title compound. MS (m/e):326.2 ([M−H]⁻, 100%)

EXAMPLE 6.14 Preparation of 5-cyclopropanesulfonyl-2-isopropoxy-benzoicacid

(a) 2-Hydroxy-5-sulfino-benzoic acid

To 317 mmol sodium sulfite in 200 ml water at RT was added dropwise over30 min a solution of 42.3 mmol 5-chlorosulfonyl-2-hydroxy-benzoic acidin 80 ml dioxane and stirring continued for a further 30 min. 5 M aqNaOH was then added dropwise until the reaction mixture was pH 14, andthe mixture was then allowed to stir at RT for a further 2 h. Themixture was then cooled to 0° C. and concentrated H₂SO₄ added until thereaction mixture was pH 1. Ethyl acetate was added, and the phases wereseparated. The organic phase was dried with Na₂SO₄. Evaporation in vacuoyielded the title compound.

MS (m/e): 201.0 ([M−H]⁻, 100%)

(b) 5-(3-Chloro-propane-1-sulfonyl)-2-hydroxy-benzoic acid

To 16.7 mmol 2-hydroxy-5-sulfino-benzoic acid and 41.7 mmoltriethylamine in 40 ml DMF was added 18.3 mmol 1-chloro-3-iodopropane,and the mixture heated at 40° C. for 1 h. The mixture was then cooled toroom temperature and concentrated in vacuo. The residue waschromatographed on silica gel (eluant: dichloromethane/methanol/aceticacid gradient) to afford the title compound. MS (m/e): 279.1([{³⁷Cl}M−H]⁻, 33%), 277.0 ([{³⁵Cl}M−H]⁻, 100%)

(c) 5-Cyclopropanesulfonyl-2-hydroxy-benzoic acid

To 8.0 mmol 5-(3-chloro-propane-1-sulfonyl)-2-hydroxy-benzoic acid in 30ml THF at −78° C. was added dropwise over 30 min 23.9 mmol of a 0.9 Msolution of potassium bis(trimethylsilyl)amide in toluene. The reactionmixture was then allowed to warm to RT and stirring continued for afurther 30 min at RT. The mixture was then diluted with THF/ethylacetate (1:1) and washed sequentially with 1 M aq HCl and saturatedaqueous NaCl solution, dried with Na₂SO₄, and concentrated in vacuo. Theresidue was triturated in ether/pentane to afford the title compound. MS(m/e): 241.2 ([M−H]⁻, 100%)

(d) 5-Cyclopropanesulfonyl-2-hydroxy-benzoic acid methyl ester

To 7.2 mmol 5-cyclopropanesulfonyl-2-hydroxy-benzoic acid in 20 mldichloroethane containing a few drops of DMF was added dropwise 8.7 mmoloxalyl chloride. After stirring for 90 min at RT, the reaction mixturewas cooled to 0° C. and then 144 mmol methanol was added, followed by 72mmol pyridine, and stirring continued at RT for 1 h. The mixture wasthen washed with 1 M aq HCl, dried with Na₂SO₄, and concentrated invacuo. The residue was chromatographed on silica gel (eluant: ethylacetate/heptane gradient) to afford the title compound. MS (m/e): 255.2([M−H]⁻, 100%)

(e) 5-Cyclopropanesulfonyl-2-isopropoxy-benzoic acid

To 0.6 mmol 5-cyclopropanesulfonyl-2-hydroxy-benzoic acid methyl ester,3.7 mmol 2-propanol and 0.9 mmol diphenyl-2-pyridylphosphine in 8 ml THFwas added 0.9 mmol di-tert-butyl azodicarboxylate, and the mixture wasstirred at RT for 3 h. 4 mmol 5 M aq NaOH solution was then added, andthe mixture heated at 60° C. for 1 h. The mixture was then concentratedin vacuo. The residue was resuspended in ethyl acetate and washed twicewith 1 M aq NaOH solution. The combined aqueous phases were thenacidified to pH 1 by addition of 25% aq HCl and extracted three timeswith ethyl acetate. The combined organic extracts were then dried withNa₂SO₄, and concentrated in vacuo to afford the tide compound. MS (m/e):282.9 ([M−H]⁻, 100%)

In analogy to Example 6.14 (e), compounds 6.15 to 6.18 of the followingtable were prepared from 5-cyclopropanesulfonyl-2-hydroxy-benzoic acidmethyl ester and the appropriate alcohol, followed by hydrolysis withaqueous sodium hydroxide:

Expl. No Systematic Name alcohol MS (m/e) 6.15 5-Cyclopropanesulfonyl-2-Methyl-1-propanol 297.1 2-isobutoxy-benzoic acid (M − H) 6.162-Cyclopentyloxy-5- Cyclopentanol 309.1 cyclopropanesulfonyl- (M − H)benzoic acid 6.17 5-Cyclopropanesulfonyl- Cyclopropyl-methanol 295.22-cyclopropylmethoxy- (M − H) benzoic acid 6.18 2-Cyclobutoxy-5-Cyclobutanol 295.2 cyclopropanesulfonyl- (M − H) benzoic acid

EXAMPLE 6.12 Preparation of1-(4-ethanesulfonyl-2-fluoro-phenyl)-piperazine

(a) 3,4-Difluoro-benzenesulfinic acid

To 2.47 mol sodium sulfite in 1120 ml water at RT was added dropwiseover 20 min a solution of 329 mmol 3,4-difluoro-benzenesulfonyl chloridein 560 ml dioxane and stirring continued for a further 30 min. 1 M aqNaOH was then added dropwise until the reaction mixture was pH 14, andthe mixture was then allowed to stir at RT for a further 16 h. Themixture was then cooled to 0° C. and concentrated H₂SO₄ added until thereaction mixture was pH 1. The mixture was extracted three times withethyl acetate, and the combined organic phases washed with saturated aqNaCl solution and then dried with Na₂SO₄. Evaporation in vacuo yieldedthe title compound. MS (m/e): 177.1 ([M−H]⁻, 100%)

(b) 4-Ethanesulfonyl-1,2-difluoro-benzene

To 3.0 mmol 3,4-difluoro-benzenesulfinic acid and 3.0 mmol triethylaminein 10 ml DMF was added 7.5 mmol iodoethane and the mixture heated at 90°C. for 9 h. The reaction mixture was then poured onto water andextracted three times with ethyl acetate. The combined organic phaseswere then washed twice with saturated aq. NaCl solution, dried overNa₂SO₄, and concentrated in vacuo. The residue was chromatographed onsilica gel (eluant: ethyl acetate/heptane 1:7) to afford the titlecompound. MS (m/e): 206.9 (M+H⁺, 100%)

(c) 1-(4-Ethanesulfonyl-2-fluoro-phenyl)-piperazine

To 2.0 mmol 4-ethanesulfonyl-1,2-difluoro-benzene in 5 mlN,N-dimethylacetamide was added 5.6 mmol piperazine and the mixture washeated at 80° C. for 45 min. The mixture was then concentrated in vacuoto afford the title compound. MS (m/e): 273.0 (M+H⁺, 100%)

In analogy to Example 6.12 (b) and (c), compounds 6.13, and 6.21 to 6.23of the following table were prepared from 3,4-difluoro-benzenesulfinicacid and the indicated alkyl halides, followed by reaction withpiperazine:

MW Expl. found No. Systematic Name alkyl halide (M + H⁺) 6.131-[4-(Butane-1-sulfonyl)-2- Iodobutane 301.1 fluoro-phenyl]-piperazine6.21 1-[2-Fluoro-4-(propane-2- 2-Iodopropane 287.0sulfonyl)-phenyl]-piperazine 6.22 1-(4- Bromomethyl- 299.2Cyclopropylmethanesulfonyl-2- cylopropane and fluoro-phenyl)-piperazineNaI 6.23 1-[2-Fluoro-4-(2-methoxy- 1-Iodo-2-methoxy- 303.1ethanesulfonyl)-phenyl]- ethane piperazine

EXAMPLE 6.20 Preparation of1-(4-Cyclopropanesulfonyl-2-fluoro-phenyl)-piperazine

(a) 4-(3-Chloro-propane-1-sulfonyl)-1,2-difluoro-benzene

To 28.3 mmol 3,4-difluoro-benzenesulfinic acid and 36.8 mmoltriethylamine in 100 ml DMF was added 70.7 mmol 1-chloro-3-iodopropaneand the mixture stirred at RT for 1 h. The reaction mixture was thenpoured onto water and extracted three times with ethyl acetate. Thecombined organic phases were then washed with saturated aq. NaClsolution, dried over Na₂SO₄, and concentrated in vacuo. The residue waschromatographed on silica gel (eluant: ethyl acetate/heptane gradient)to afford the title compound.

MS (m/e): 257.2 ({³⁷Cl}M+H⁺, 33%), 255.1({³⁵Cl}M+H⁺, 100%),

(b) 4-Cyclopropanesulfonyl-1,2-difluoro-benzene

To 11.8 mmol 4-(3-chloro-propane-1-sulfonyl)-1,2-difluoro-benzene in 400ml THF at −78° C. was added dropwise over 30 min 14.2 mmol of a 0.9 Msolution of potassium bis(trimethylsilyl)amide in THF. The reactionmixture was then allowed to warm to RT and stirring continued for afurther 30 min at RT. The mixture was then quenched by addition of 1 Maq HCl and extracted three times with ethyl acetate. The combinedorganic phases were dried with Na₂SO₄, and concentrated in vacuo. Theresidue was chromatographed on silica gel (eluant: ethyl acetate/heptane1:5) to afford the title compound. MS (m/e): 219.2 (M+H⁺, 100%)

(c) 1-(4-Cyclopropanesulfonyl-2-fluoro-phenyl)-piperazine

To 0.2 mmol 4-cyclopropanesulfonyl-1,2-difluoro-benzene in 5 mlN,N-dimethylacetamide was added 0.5 mmol piperazine and the mixture washeated at 80° C. for 90 min. The mixture was then concentrated in vacuoto afford the title compound. MS (m/e): 285.0 (M+H⁺, 100%)

EXAMPLE 6.24 Preparation of1-(4-cyclobutanesulfonyl-2-fluoro-phenyl)-piperazine hydrochloride

(a) 4-Cyclobutanesulfonyl-1,2-difluoro-benzene

To 5.6 mmol 3,4-difluoro-benzenesulfinic acid and 6.2 mmol triethylaminein 10 ml DMF were added 8.4 mmol bromocyclobutane and 0.2 mmol sodiumiodide and the mixture heated at 100° C. for 48 h. The reaction mixturewas then poured onto water and extracted three times with ethyl acetate.The combined organic phases were then washed with saturated aq. NaClsolution, dried over Na₂SO₄, and concentrated in vacuo. The residue waschromatographed on silica gel (eluant: ethyl acetate/heptane gradient)to afford the title compound. MS (m/e): 233.1 (M+H⁺, 100%)

(b) 1-(4-Cyclobutanesulfonyl-2-fluoro-phenyl)-piperazine hydrochloride

To 2.8 mmol 4-cyclobutanesulfonyl-1,2-difluoro-benzene in 20 mlN,N-dimethylacetamide was added 8.3 mmol piperazine, and the mixture washeated at 80° C. for 45 min. The mixture was then concentrated in vacuo,and the residue was chromatographed on silica gel (eluant: ethylacetate/methanol gradient). The product-containing fractions werecombined and concentrated in vacuo. The residue was resuspended in 100ml dioxane, and 6.0 mmol HCl (as a 4 M solution in dioxane) was added.After stirring for 10 min, the ensuing white crystals were collected byfiltration, washing twice with ether, to afford the title compound.

MS (m/e): 299.1 (M+H⁺, 100%)

In analogy to Example 6.24 (a) and (b), compound 6.25 of the followingtable was prepared from the 3,4-difluoro-benzenesulfinic acid,bromocyclobutane and sodium iodide, followed by reaction with piperazineand subsequent treatment with HCl in dioxane:

MW found Expl. No Systematic Name Starting Materials (M + H⁺) 6.25 1-(4-difluoro- 313.3 Cyclopentanesulfonyl-2- benzenesulfinic acidfluoro-phenyl)-piperazine and hydrochloride) bromocyclopentane

EXAMPLE 6.26 Preparation of1-[2-fluoro-4-(3,3,3-trifluoro-propane-1-sulfonyl)-phenyl]-piperazine

(a) 1,2-Difluoro-4-(3,3,3-trifluoro-propylsulfanyl)-benzene

To 3.4 mmol 3,4-difluoro-thiophenol and 5.1 mmol1-iodo-3,3,3-trifluoropropane in 5 ml acetone was added 3.7 mmolpotassium carbonate, and the mixture heated at 140° C. for 3 h undermicrowave irradiation. The reaction mixture was then poured onto waterand extracted three times with ethyl acetate. The combined organicphases were then washed with saturated aq. NaCl solution, dried overNa₂SO₄, and concentrated in vacuo to afford the title compound. MS(m/e): 243.1 (M+H⁺, 100%)

(b) 1,2-Difluoro-4-(3,3,3-trifluoro-propane-1-sulfonyl)-benzene

To 3.0 mmol 1,2-difluoro-4-(3,3,3-trifluoro-propylsulfanyl)-benzene in 5ml dichloromethane was added 8.3 mmol m-chloroperbenzoic acid, and themixture heated at 50° C. for 48 h. The reaction mixture was then cooledto room temperature and diluted with dichloromethane and washed threetimes with saturated aq NaHCO3 solution. The organic phase was thenwashed with saturated aq. NaCl solution, dried over Na₂SO₄, andconcentrated in vacuo. The residue was chromatographed on silica gel(eluant: ethyl acetate/heptane gradient) to afford the title compound.MS (m/e): 275.1 (M+H⁺, 100%)

(c)1-[2-Fluoro-4-(3,3,3-trifluoro-propane-1-sulfonyl)-phenyl]-piperazine

To 0.5 mmol 1,2-difluoro-4-(3,3,3-trifluoro-propane-1-sulfonyl)-benzenein 5 ml N,N-dimethylacetamide was added 1.5 mmol piperazine, and themixture was heated at 80° C. for 90 min. The mixture was thenconcentrated in vacuo, and the residue was chromatographed on silica gel(eluant: methanol/dichloromethane gradient) to afford the titlecompound. MS (m/e): 341.2 (M+H⁺, 100%)

In analogy to Example 6.26 (a) to (c), compounds 6.27 and 6.28 of thefollowing table were prepared from 3,4-difluoro-thiophenol and theindicated alkylating agent, followed by oxidation withm-chloroperbenzoic acid and reaction with piperazine:

MW found Expl No Systematic name Alkylating agent (M + H⁺) 6.271-[2-Fluoro-4- Toluene-4-sulfonic acid 329.1 (tetrahydro-pyran-4-tetrahydro-pyran-4-yl sulfonyl)-phenyl]- ester piperazine 6.28 1-(4-Iodocyclohexane 327.3 Cyclohexanesulfonyl- 2-fluoro-phenyl)- piperazine

EXAMPLE 6.29 Preparation of1-[2,3-difluoro-4-(propane-2-sulfonyl)-phenyl]-piperazine hydrochloride

(a) 1,2,3-Trifluoro-4-(propane-2-sulfonyl)-benzene

To 20.4 mmol 2,3,4-trifluoro-benzenesulfinic acid (prepared in analogyto example 2.20(a) from 2,3,4-trifluoro-benzenesulfonyl chloride) and61.2 mmol triethylamine in 20 ml DMF was added 40.8 mmol 2-iodopropane,and the mixture stirred at room temperature for 16 h. The reactionmixture was then poured onto water and extracted three times with ethylacetate. The combined organic phases were then washed twice withsaturated aq. NaCl solution, dried over Na₂SO₄, and concentrated invacuo. The residue was chromatographed on silica gel (eluant: ethylacetate/heptane 1:4) to afford the title compound.

MS (m/e): 239.1 (M+H⁺, 100%)

(b)4-[2,3-Difluoro-4-(propane-2-sulfonyl)-phenyl]-piperazine-1-carboxylicacid tert-butyl ester

To 7.6 mmol 1,2,3-trifluoro-4-(propane-2-sulfonyl)-benzene in 20 mlN,N-dimethylacetamide was added 15.9 mmol tert-butyl-1-piperazinecarboxylate, and the mixture was heated at 90° C. for 1 h. The mixturewas then cooled to room temperature and concentrated in vacuo. Theresidue was chromatographed on silica gel (eluant: ethyl acetate/heptane1:2) to afford the title compound.

MS (m/e): 405.2 (M+H⁺, 100%)

(c) 1-[2,3-Difluoro-4-(propane-2-sulfonyl)-phenyl]-piperazinehydrochloride

To 7.5 mmol4-[2,3-difluoro-4-(propane-2-sulfonyl)-phenyl]-piperazine-1-carboxylicacid tert-butyl ester in 100 ml dioxane was added 30.2 mmol HCl (as a 4M solution in dioxane), and the mixture was heated at 80° C. for 1 h.The mixture was then cooled to room temperature, and the ensuing whitecrystals were collected by filtration, washing twice with ether, toafford the title compound.

MS (m/e): 305.2 (M+H⁺, 100%)

In analogy to Example 6.29 (a) to (c), compounds 6.30, 6.32 and 6.33 ofthe following table were prepared from the indicated sulfinic acids andalkyl halides, followed by reaction with tert-butyl-1-piperazinecarboxylate and hydrolysis with HCl in dioxane:

MW Expl. found No Systematic Name starting materials (M + H) 6.301-(4-Ethanesulfonyl-2,3- 2,3,4-trifluoro- 291.2difluoro-phenyl)-piperazine benzenesulfinic acid and hydrochlorideiodoethane 6.32 1-[2,5-Difluoro-4- 2,4,5-Trifluoro- 305.1(propane-2-sulfonyl)- benzenesulfinic acid and phenyl]-piperazine2-iodopropane hydrochloride 6.33 1-(4-Ethanesulfonyl-2,5-2,4,5-Trifluoro- 291.1 difluoro-phenyl)-piperazine benzenesulfinic acidand hydrochloride iodoethane

EXAMPLE 6.31 Preparation of1-(4-cyclopropanesulfonyl-2,3-difluoro-phenyl)-piperazine hydrochloride

(a) 1-(3-Chloro-propane-1-sulfonyl)-2,3,4-trifluoro-benzene

To 30.6 mmol 2,3,4-trifluoro-benzenesulfinic acid (acid (prepared inanalogy to example 2.20(a) from 2,3,4-trifluoro-benzenesulfonylchloride) and 91.8 mmol triethylamine in 20 ml DMF was added 61.2 mmol1-chloro-3-iodopropane, and the mixture stirred at room temperature for1 h. The reaction mixture was then poured onto water and extracted threetimes with ethyl acetate. The combined organic phases were then washedtwice with saturated aq. NaCl solution, dried over Na₂SO₄, andconcentrated in vacuo. The residue was chromatographed on silica gel(eluant: ethyl acetate/heptane 1:4) to afford the title compound. MS(m/e): 275.2 ({³⁷Cl}M+H⁺, 33%), 273.1({³⁵Cl}M+H⁺, 100%),

(b) 1-Cyclopropanesulfonyl-2,3,4-trifluoro-benzene

To 5.9 mmol 1-(3-chloro-propane-1-sulfonyl)-2,3,4-trifluoro-benzene in200 ml THF at −78° C. was added dropwise over 30 min 7.0 mmol of a 0.9 Msolution of potassium bis(trimethylsilyl)amide in THF. The reactionmixture was then allowed to warm to RT, and stirring continued for afurther 30 min at RT. The mixture was then quenched by addition of 1 Maq HCl and extracted three times with ethyl acetate. The combinedorganic phases were dried with Na₂SO₄, and concentrated in vacuo. Theresidue was chromatographed on silica gel (eluant: ethyl acetate/heptane1:4) to afford the title compound. MS (m/e): 237.2 (M+H⁺, 100%)

(c)4-(4-Cyclopropanesulfonyl-2,3-difluoro-phenyl)-piperazine-1-carboxylicacid tert-butyl ester

To 4.2 mmol 1-cyclopropanesulfonyl-2,3,4-trifluoro-benzene in 20 mlN,N-dimethylacetamide was added 8.9 mmol tert-butyl-1-piperazinecarboxylate, and the mixture was heated at 90° C. for 1 h. The mixturewas then cooled to room temperature and concentrated in vacuo. Theresidue was chromatographed on silica gel (eluant: dichloromethane/ethylacetate gradient) to afford the title compound. MS (m/e): 403.3 (M+H⁺,100%)

(d) 1-(4-Cyclopropanesulfonyl-2,3-difluoro-phenyl)-piperazinehydrochloride

To 3.7 mmol4-(4-Cyclopropanesulfonyl-2,3-difluoro-phenyl)-piperazine-1-carboxylicacid tert-butyl ester in 100 ml dioxane was added 14.9 mmol HCl (as a 4M solution in dioxane), and the mixture was heated at 80° C. for 1 h.The mixture was then cooled to room temperature, and the ensuing whitecrystals were collected by filtration, washing twice with ether, toafford the title compound. MS (m/e): 303.2 (M+H⁺, 100%)

In analogy to Example 6.31 (a) to (d), compound 6.34 of the followingtable was prepared from the indicated sulfinic acid and alkyl halide,followed by treatment with potassium bis(trimethylsilyl)amide, reactionwith tert-butyl-1-piperazine carboxylate and deprotection with HCl indioxane:

MW Expl. found No Systematic Name starting materials (M + H) 6.341-(4-Cyclopropanesulfonyl-2,5- 2,4,5-Trifluoro- 303.1difluoro-phenyl)-piperazine benzenesulfinic hydrochloride acid and 2-iodopropane

EXAMPLE 6.35 Preparation ofrac-2-Methyl-1-(4-trifluoromethyl-phenyl)-piperazine hydrochloride

(a) rac-3-Methyl-4-(4-trifluoromethyl-phenyl)-piperazine-1-carboxylicacid tert-butyl ester

To 1-bromo-4-trifluoromethyl-benzene (1 g),rac-3-Methyl-piperazine-1-carboxylic acid tert-butyl ester (1 g), intoluene (10 mL) was added sodium tert-butylate (0.6 g),2-(dicyclohexylphosphino)biphenyl (31 mg), andtris(dibenzylideneacetone)Pd-CHCl₃ (23 mg). The reaction mixture wasthen stirred at 80° C. overnight. Ethyl acetate was then added to thereaction mixture. Solids were filtered off. The filtrate was thenconcentrated in vacuo, and the residue was purified by columnchromatography to yield 0.46 g of the title compound. MS (m/e): 345.2(M+H⁺, 100%)

(b) rac-2-Methyl-1-(4-trifluoromethyl-phenyl)-piperazine hydrochloride

To 0.58 mmolrac-3-methyl-4-(4-trifluoromethyl-phenyl)-piperazine-1-carboxylic acidtert-butyl ester in 3 ml dioxane was added 8.7 mmol HCl (as a 4 Msolution in dioxane), and the mixture was heated at 90° C. for 3 h. Themixture was then cooled 0° C. and diluted with 10 ml ether. The ensuingwhite crystals were collected by filtration, washing with ether, anddried in vacuo to afford the title compound.

MS (m/e): 245.1 (M+H⁺, 100%)

EXAMPLE 6.36 Preparation of 5-Acetyl-2-isopropoxy-benzoic acid

(a) 5-Acetyl-2-isopropoxy-benzoic acid methyl ester

To 25.8 mmol methyl-5-acetyl-2-hydroxybenzoate, 28.3 mmol 2-propanol and29.6 mmol triphenylphosphine in 100 ml THF was added 28.3 mmoldi-tert-butyl azodicarboxylate, and the mixture was stirred at RT for 90min. The mixture was then concentrated in vacuo to afford the titlecompound. MS (m/e): 237.1 (M+H⁺, 100%)

(b) 5-Acetyl-2-isopropoxy-benzoic acid

To 25.8 mmol 5-acetyl-2-isopropoxy-benzoic acid methyl ester in 100 mlTHF was 400 mmol 2 M aq NaOH, and the mixture was heated at 80° C. for 2h. The mixture en cooled to RT and extracted twice with ether. Theaqueous phase was acidified with q hydrochloric acid and extracted 3times with ethyl acetate. The combined organic were dried with Na₂SO₄.Evaporation in vacuo followed by trituration in ether ed the titlecompound. MS (m/e): 221.2 ([M−H]⁻, 100%)

In analogy to Example 5 compounds 472 to 619 of the following table wereed from the acid derivatives and piperazine derivatives:

Expl. MW found No. Systematic Name Starting materials (MH⁺) 4723-[4-(4-Cyano-2-fluoro- 3-Fluoro-4-piperazin-1-yl- 433.2phenyl)-piperazine-1- benzonitrile (WO9625414) and 2-carbonyl]-4-ethoxy- Ethoxy-5-sulfamoyl-benzoic acid benzenesulfonamide(JP53050139) 473 3-[4-(4-Cyano-3-fluoro- 2-Fluoro-4-piperazin-1-yl-431.3 phenyl)-piperazine-1- benzonitrile (WO 9808835) and 2- (M − H)carbonyl]-4-ethoxy- Ethoxy-5-sulfamoyl-benzoic acid benzenesulfonamide(JP53050139) 474 3-[4-(4-Cyano-phenyl)- 4-Piperazin-1-yl-benzonitrile413.3 piperazine-1-carbonyl]- (commercial) and 2-Ethoxy-5- (M − H)4-ethoxy- sulfamoyl-benzoic acid (JP53050139) benzenesulfonamide 4753-[4-(4-Cyano-3-fluoro- 2-Fluoro-4-piperazin-1-yl- 475.1phenyl)-piperazine-1- benzonitrile (WO 9808835) and 2-carbonyl]-4-isobutoxy- Isobutoxy-5-methylsulfamoyl- N-methyl- benzoicacid (compound 6.1) benzenesulfonamide 476 3-[4-(4-Cyano-3-fluoro-2-Fluoro-4-piperazin-1-yl- 489.3 phenyl)-piperazine-1- benzonitrile (WO9808835) and 2- carbonyl]-4-(2,2- (2,2-Dimethyl-propoxy)-5-dimethyl-propoxy)-N- methylsulfamoyl-benzoic acid methyl- (compound 6.2)benzenesulfonamide 477 3-[4-(4-Cyano-3-fluoro-2-Fluoro-4-piperazin-1-yl- 461.2 phenyl)-piperazine-1- benzonitrile (WO9808835) and 2- carbonyl]-4-isopropoxy- Isopropoxy-5-methylsulfamoyl-N-methyl- benzoic acid (compound 6.3) benzenesulfonamide 4783-[4-(4-Cyano-3-fluoro- 2-Fluoro-4-piperazin-1-yl- 487.3phenyl)-piperazine-1- benzonitrile (WO 9808835) and 2- carbonyl]-4-Cyclopentyloxy-5-methylsulfamoyl- cyclopentyloxy-N- benzoic acid(compound 6.4) methyl-benzenesulfonamide 479 3-[4-(4-Cyano-3-fluoro-2-Fluoro-4-piperazin-1-yl- 473.1 phenyl)-piperazine-1- benzonitrile (WO9808835) and 2- carbonyl]-4-cyclobutoxy- Cyclobutoxy-5-methylsulfamoyl-N-methyl- benzoic acid (compound 6.5) benzenesulfonamide 4803-[4-(4-Cyano-3-fluoro- 2-Fluoro-4-piperazin-1-yl- 473.2phenyl)-piperazine-1- benzonitrile (WO 9808835) and 2- carbonyl]-4-Cyclopropylmethoxy-5- cyclopropylmethoxy-N- methylsulfamoyl-benzoic acidmethyl-benzenesulfonamide (compound 6.6) 481 3-[4-(4-Cyano-3-fluoro-2-Fluoro-4-piperazin-1-yl- 487.3 phenyl)-piperazine-1- benzonitrile (WO9808835) and 2- carbonyl]-4- Cyclobutylmethoxy-5- cyclobutylmethoxy-N-methylsulfamoyl-benzoic acid methyl-benzenesulfonamide (compound 6.7)482 3-[4-(4-Cyano-3-fluoro- 2-Fluoro-4-piperazin-1-yl- 503.2phenyl)-piperazine-1- benzonitrile (WO 9808835) and 5-carbonyl]-N-methyl-4- Methylsulfamoyl-2-(tetrahydro-(tetrahydro-pyran-4- pyran-4-yloxy)-benzoic acidyloxy)-benzenesulfonamide (compound 6.8) 483 3-[4-(4-Cyano-3-fluoro-2-Fluoro-4-piperazin-1-yl- 477.3 phenyl)-piperazine-1- benzonitrile (WO9808835) and 2- carbonyl]-4-(2-methoxy- (2-Methoxy-ethoxy)-5-ethoxy)-N-methyl- methylsulfamoyl-benzoic acid benzenesulfonamide(compound 6.9) 484 3-[4-(4-Cyano-3-fluoro- 2-Fluoro-4-piperazin-1-yl-515.2 phenyl)-piperazine-1- benzonitrile (WO 9808835) and 5-carbonyl]-N-methyl-4- Methylsulfamoyl-2-(3,3,3-trifluoro-(3,3,3-trifluoro- propoxy)-benzoic acid (compound propoxy)- 6.10)benzenesulfonamide 485 3-[4-(4-Cyano-phenyl)-4-Piperazin-1-yl-benzonitrile 459.1 piperazine-1-carbonyl]- (commercial)and 2-(2-Methoxy- 4-(2-methoxy-ethoxy)-ethoxy)-5-methylsulfamoyl-benzoic N-methyl- acid (compound 6.9)benzenesulfonamide 486 3-[4-(4-Cyano-phenyl)-4-Piperazin-1-yl-benzonitrile 497.0 piperazine-1-carbonyl]- (commercial)and 5- N-methyl-4-(3,3,3- Methylsulfamoyl-2-(3,3,3-trifluoro-trifluoro-propoxy)- propoxy)-benzoic acid (compound benzenesulfonamide6.10) 487 3-[4-(4-Cyano-phenyl)- 4-Piperazin-1-yl-benzonitrile 485.2piperazine-1-carbonyl]- (commercial) and 5- N-methyl-4-(tetrahydro-Methylsulfamoyl-2-(tetrahydro- pyran-4-yloxy)- pyran-4-yloxy)-benzoicacid benzenesulfonamide (compound 6.8) 488 3-[4-(4-Cyano-phenyl)-4-Piperazin-1-yl-benzonitrile 457.3 piperazine-1-carbonyl]- (commercial)and 2-Isobutoxy-5- 4-isobutoxy-N-methyl- methylsulfamoyl-benzoic acidbenzenesulfonamide (compound 6.1) 489 3-[4-(4-Cyano-phenyl)-4-Piperazin-1-yl-benzonitrile 471.1 piperazine-1-carbonyl]- (commercial)and 2-(2,2-Dimethyl- 4-(2,2-dimethyl- propoxy)-5-methylsulfamoyl-propoxy)-N-methyl- benzoic acid (compound 6.2) benzenesulfonamide 4903-[4-(4-Cyano-phenyl)- 4-Piperazin-1-yl-benzonitrile 443.2piperazine-1-carbonyl]- (commercial) and 2-Isopropoxy-5-4-isopropoxy-N-methyl- methylsulfamoyl-benzoic acid benzenesulfonamide(compound 6.3) 491 3-[4-(4-Cyano-phenyl)- 4-Piperazin-1-yl-benzonitrile469.2 piperazine-1-carbonyl]- (commercial) and 2-Cyclopentyloxy-4-cyclopentyloxy-N- 5-methylsulfamoyl-benzoic acidmethyl-benzenesulfonamide (compound 6.4) 492 3-[4-(4-Cyano-phenyl)-4-Piperazin-1-yl-benzonitrile 455.3 piperazine-1-carbonyl]- (commercial)and 2-Cyclobutoxy-5- 4-cyclobutoxy-N-methyl- methylsulfamoyl-benzoicacid benzenesulfonamide (compound 6.5) 493 3-[4-(4-Cyano-phenyl)-4-Piperazin-1-yl-benzonitrile 455.3 piperazine-1-carbonyl]- (commercial)and 2- 4-cyclopropylmethoxy- Cyclopropylmethoxy-5- N-methyl-methylsulfamoyl-benzoic acid benzenesulfonamide (compound 6.6) 4943-[4-(4-Cyano-phenyl)- 4-Piperazin-1-yl-benzonitrile 469.2piperazine-1-carbonyl]- (commercial) and 2- 4-cyclobutylmethoxy-N-Cyclobutylmethoxy-5- methyl-benzenesulfonamide methylsulfamoyl-benzoicacid (compound 6.7) 495 3-[4-(2-Fluoro-4- 1-(2-Fluoro-4-methanesulfonyl-528.0 methanesulfonyl- phenyl)-piperazine (commercial)phenyl)-piperazine-1- and 2-Isobutoxy-5- carbonyl]-4-isobutoxy-methylsulfamoyl-benzoic acid N-methyl- (compound 6.1) benzenesulfonamide496 4-(2,2-Dimethyl- 1-(2-Fluoro-4-methanesulfonyl- 559.2propoxy)-3-[4-(2-fluoro- phenyl)-piperazine (commercial) (M + NH4+)4-methanesulfonyl- and 2-(2,2-Dimethyl-propoxy)-5- phenyl)-piperazine-1-methylsulfamoyl-benzoic acid carbonyl]-N-methyl- (compound 6.2)benzenesulfonamide 497 3-[4-(2-Fluoro-4- 1-(2-Fluoro-4-methanesulfonyl-514.1 methanesulfonyl- phenyl)-piperazine (commercial)phenyl)-piperazine-1- and 2-Isopropoxy-5- carbonyl]-4-isopropoxy-methylsulfamoyl-benzoic acid N-methyl- (compound 6.3) benzenesulfonamide498 4-Cyclopentyloxy-3-[4- 1-(2-Fluoro-4-methanesulfonyl- 557.0(2-fluoro-4- phenyl)-piperazine (commercial) (M + NH4+) methanesulfonyl-and 2-Cyclopentyloxy-5- phenyl)-piperazine-1- methylsulfamoyl-benzoicacid carbonyl]-N-methyl- (compound 6.4) benzenesulfonamide 4994-Cyclobutoxy-3-[4-(2- 1-(2-Fluoro-4-methanesulfonyl- 526.0 fluoro-4-phenyl)-piperazine (commercial) methanesulfonyl- and 2-Cyclobutoxy-5-phenyl)-piperazine-1- methylsulfamoyl-benzoic acid carbonyl]-N-methyl-(compound 6.5) beuzenesulfonamide 500 4-Cyclopropylmethoxy-1-(2-Fluoro-4-methanesulfonyl- 526.0 3-[4-(2-fluoro-4-phenyl)-piperazine (commercial) methanesulfonyl- and2-Cyclopropylmethoxy-5- phenyl)-piperazine-1- methylsulfamoyl-benzoicacid carbonyl]-N-methyl- (compound 6.6) benzenesulfonamide 5014-Cyclobutylmethoxy-3- 1-(2-Fluoro-4-methanesulfonyl- 557.0[4-(2-fluoro-4- phenyl)-piperazine (commercial) (M + NH4+)methanesulfonyl- and 2-Cyclobutylmethoxy-5- phenyl)-piperazine-1-methylsulfamoyl-benzoic acid carbonyl]-N-methyl- (compound 6.7)benzenesulfonamide 502 3-[4-(2-Fluoro-4- 1-(2-Fluoro-4-methanesulfonyl-530.1 methanesulfonyl- phenyl)-piperazine (commercial)phenyl)-piperazine-1- and 2-(2-Methoxy-ethoxy)-5-carbonyl]-4-(2-methoxy- methylsulfamoyl-benzoic acid ethoxy)-N-methyl-(compound 6.9) benzenesulfonamide 503 3-[4-(2-Fluoro-4-1-(2-Fluoro-4-methanesulfonyl- 585.0 methanesulfonyl- phenyl)-piperazine(commercial) (M + NH4+) phenyl)-piperazine-1- and5-Methylsulfamoyl-2-(3,3,3- carbonyl]-N-methyl-4-trifluoro-propoxy)-benzoic acid (3,3,3-trifluoro-propoxy)- (compound6.10) benzenesulfonamide 504 3-[4-(4-Cyano-2-fluoro-3-Fluoro-4-piperazin-1-yl- 475.0 phenyl)-piperazine-1- benzonitrile(WO9625414) and 2- carbonyl]-4-isobutoxy- Isobutoxy-5-methylsulfamoyl-N-methyl- benzoic acid (compound 6.1) benzenesulfonamide 5053-[4-(4-Cyano-2-fluoro- 3-Fluoro-4-piperazin-1-yl- 489.0phenyl)-piperazine-1- benzonitrile (WO9625414) and 2- carbonyl]-4-(2,2-(2,2-Dimethyl-propoxy)-5- dimethyl-propoxy)-N- methylsulfamoyl-benzoicacid methyl-benzenesulfonamide (compound 6.2) 5063-[4-(4-Cyano-2-fluoro- 3-Fluoro-4-piperazin-1-yl- 478.0phenyl)-piperazine-1- benzonitrile (WO9625414) and 2- (M + NH4+)carbonyl]-4-isopropoxy- Isopropoxy-5-methylsulfamoyl- N-methyl- benzoicacid (compound 6.3) benzenesulfonamide 507 3-[4-(4-Cyano-2-fluoro-3-Fluoro-4-piperazin-1-yl- 487.1 phenyl)-piperazine-1- benzonitrile(WO9625414) and 2- carbonyl]-4- Cyclopentyloxy-5-methylsulfamoyl-cyclopentyloxy-N-methyl- benzoic acid (compound 6.4) benzenesulfonamide508 3-[4-(4-Cyano-2-fluoro- 3-Fluoro-4-piperazin-1-yl- 472.8phenyl)-piperazine-1- benzonitrile (WO9625414) andcarbonyl]-4-cyclobutoxy- Cyclobutoxy-5-methylsulfamoyl- N-methyl-benzoic acid (compound 6.5) benzenesulfonamide 5093-[4-(4-Cyano-2-fluoro- 3-Fluoro-4-piperazin-1-yl- 472.8phenyl)-piperazine-1- benzonitrile (WO9625414) and 2- carbonyl]-4-Cyclopropylmethoxy-5- cyclopropylmethoxy-N- methylsulfamoyl-benzoic acidmethyl-benzenesulfonamide (compound 6.6) 510 3-[4-(4-Cyano-2-fluoro-3-Fluoro-4-piperazin-1-yl- 487.1 phenyl)-piperazine-1- benzonitrile(WO9625414) and 2- carbonyl]-4- Cyclobutylmethoxy-5-cyclobutylmethoxy-N- methylsulfamoyl-benzoic acidmethyl-benzenesulfonamide (compound 6.7) 511 3-[4-(4-Cyano-2-fluoro-3-Fluoro-4-piperazin-1-yl- 503.0 phenyl)-piperazine-1- benzonitrile(WO9625414) and 5- carbonyl]-N-methyl-4- Methylsulfamoyl-2-(tetrahydro-(tetrahydro-pyran-4- pyran-4-yloxy)-benzoic acidyloxy)-benzenesulfonamide (compound 6.8) 512 3-[4-(4-Cyano-2-fluoro-3-Fluoro-4-piperazin-1-yl- 477.1 phenyl)-piperazine-1- benzonitrile(WO9625414) and 2-(2- carbonyl]-4-(2-methoxy- Methoxy-ethoxy)-5-ethoxy)-N-methyl- methylsulfamoyl-benzoic acid benzenesulfonamide(compound 6.9) 513 3-[4-(4-Cyano-2-fluoro- 3-Fluoro-4-piperazin-1-yl-515.1 phenyl)-piperazine-1- benzonitrile (WO9625414) and 5-carbonyl]-N-methyl-4- Methylsulfamoyl-2-(3,3,3-trifluoro-(3,3,3-trifluoro-propoxy)- propoxy)-benzoic acid (compound 6.10)benzenesulfonamide 514 3-[4-(4-Acetyl-2-fluoro-1-(3-Fluoro-4-piperazin-1-yl- 492.1 phenyl)-piperazine-1-phenyl)-ethanone (WO9714690) and carbonyl]-4-isobutoxy-2-Isobutoxy-5-methylsulfamoyl- N-methyl-benzenesulfonamide benzoic acid(compound 6.1) 515 3-[4-(4-Acetyl-2-fluoro-1-(3-Fluoro-4-piperazin-1-yl- 506.3 phenyl)-piperazine-1-phenyl)-ethanone (WO9714690) and carbonyl]-4-(2,2-2-(2,2-Dimethyl-propoxy)-5- dimethyl-propoxy)-N- methylsulfamoyl-benzoicacid methyl-benzenesulfonamide (compound 6.2) 5163-[4-(4-Acetyl-2-fluoro- 1-(3-Fluoro-4-piperazin-1-yl- 478.2phenyl)-piperazine-1- phenyl)-ethanone (WO9714690) andcarbonyl]-4-isopropoxy- 2-Isopropoxy-5-methylsulfamoyl-N-methyl-benzenesulfonamide benzoic acid (compound 6.3) 5173-[4-(4-Acetyl-2-fluoro- 1-(3-Fluoro-4-piperazin-1-yl- 504.2phenyl)-piperazine-1- phenyl)-ethanone (WO9714690) and carbonyl]-4-2-Cyclopentyloxy-5- cyclopentyloxy-N- methylsulfamoyl-benzoic acidmethyl-benzenesulfonamide (compound 6.4) 518 3-[4-(4-Acetyl-2-fluoro-1-(3-Fluoro-4-piperazin-1-yl- 590.6 phenyl)-piperazine-1-phenyl)-ethanone (WO9714690) and carbonyl]-4-cyclobutoxy-2-Cyclobutoxy-5-methylsulfamoyl- N-methyl-benzenesulfonamide benzoicacid (compound 6.5) 519 3-[4-(4-Acetyl-2-fluoro-1-(3-Fluoro-4-piperazin-1-yl- 490.2 phenyl)-piperazine-1-phenyl)-ethanone (WO9714690) and carbonyl]-4- 2-Cyclopropylmethoxy-5-cyclopropylmethoxy-N- methylsulfamoyl-benzoic acidmethyl-benzenesulfonamide (compound 6.6) 520 3-[4-(4-Acetyl-2-fluoro-1-(3-Fluoro-4-piperazin-1-yl- 504.2 phenyl)-piperazine-1-phenyl)-ethanone (WO9714690) and carbonyl]-4- 2-Cyclobutylmethoxy-5-cyclobutylmethoxy-N- methylsulfamoyl-benzoic acidmethyl-benzenesulfonamide (compound 6.7) 521 3-[4-(4-Acetyl-2-fluoro-1-(3-Fluoro-4-piperazin-1-yl- 520.3 phenyl)-piperazine-1-phenyl)-ethanone (WO9714690) and carbonyl]-N-methyl-4-5-Methylsulfamoyl-2-(tetrahydro- (tetrahydro-pyran-4-pyran-4-yloxy)-benzoic acid yloxy)-benzenesulfonamide (compound 6.8) 5223-[4-(4-Acetyl-2-fluoro- 1-(3-Fluoro-4-piperazin-1-yl- 494.2phenyl)-piperazine-1- phenyl)-ethanone (WO9714690) andcarbonyl]-4-(2-methoxy- 2-(2-Methoxy-ethoxy)-5- ethoxy)-N-methyl-methylsulfamoyl-benzoic acid benzenesulfonamide (compound 6.9) 5233-[4-(4-Acetyl-2-fluoro- 1-(3-Fluoro-4-piperazin-1-yl- 532.2phenyl)-piperazine-1- phenyl)-ethanone (WO9714690) andcarbonyl]-N-methyl-4- 5-Methylsulfamoyl-2-(3,3,3- (3,3,3-trifluoro-trifluoro-propoxy)-benzoic acid propoxy)-benzenesulfonamide (compound6.10) 524 4-Isobutoxy-N-methyl-3- 1-(4-Trifluoromethyl-phenyl)- 500.2[4-(4-trifluoromethyl- piperazine (commercial) and 2-phenyl)-piperazine-1- Isobutoxy-5-methylsulfamoyl-carbonyl]-benzenesulfonamide benzoic acid (compound 6.1) 5254-(2,2-Dimethyl- 1-(4-Trifluoromethyl-phenyl)- 514.2propoxy)-N-methyl-3- piperazine (commercial) and [4-(4-trifluoromethyl-2-(2,2-Dimethyl-propoxy)-5- phenyl)-piperazine-1-methylsulfamoyl-benzoic acid carbonyl]-benzenesulfonamide (compound 6.2)526 4-Isopropoxy-N-methyl- 1-(4-Trifluoromethyl-phenyl)- 486.23-[4-(4-trifluoromethyl- piperazine (commercial) and 2-phenyl)-piperazine-1- Isopropoxy-5-methylsulfamoyl-carbonyl]-benzenesulfonamide benzoic acid (compound 6.3) 5274-Cyclopentyloxy-N- 1-(4-Trifluoromethyl-phenyl)- 512.3 methyl-3-[4-(4-piperazine (commercial) and 2- trifluoromethyl-phenyl)-Cyclopentyloxy-5-methylsulfamoyl- piperazine-1-carbonyl]- benzoic acid(compound 6.4) benzenesulfonamide 528 4-Cyclobutoxy-N-1-(4-Trifluoromethyl-phenyl)- 498.2 methyl-3-[4-(4- piperazine(commercial) and 2- trifluoromethyl-phenyl)-Cyclobutoxy-5-methylsulfamoyl- piperazine-1-carbonyl]- benzoic acid(compound 6.5) benzenesulfonamide 529 4-Cyclopropylmethoxy-1-(4-Trifluoromethyl-phenyl)- 498.2 N-methyl-3-[4-(4- piperazine(commercial) and 2- trifluoromethyl-phenyl)- Cyclopropylmethoxy-5-piperazine-1-carbonyl]- methylsulfamoyl-benzoic acid benzenesulfonamide(compound 6.6) 530 4-Cyclobutylmethoxy-N- 1-(4-Trifluoromethyl-phenyl)-512.3 methyl-3-[4-(4- piperazine (commercial) and 2-trifluoromethyl-phenyl)- Cyclobutylmethoxy-5- piperazine-1-carbonyl]-methylsulfamoyl-benzoic acid benzenesulfonamide (compound 6.7) 531N-Methyl-3-[4-(4- 1-(4-Trifluoromethyl-phenyl)- 540.2trifluoromethyl-phenyl)- piperazine (commercial) and 5-piperazine-1-carbonyl]- Methylsulfamoyl-2-(3,3,3-trifluoro-4-(3,3,3-trifluoro- propoxy)-benzoic acid (compound 6.10)propoxy)-benzenesulfonamide 532 3-[4-(4-Cyano-3-fluoro-2-Fluoro-4-piperazin-1-yl- 501.1 phenyl)-piperazine-1- benzonitrile (WO9808835) and 5- carbonyl]-N-methyl-4-Methylsulfamoyl-2-(2,2,2-trifluoro- (2,2,2-trifluoro-ethoxy)-ethoxy)-benzoic acid (compound 6.11) benzenesulfonamide 5333-[4-(4-Cyano-phenyl)- 4-Piperazin-1-yl-benzonitrile 483.3piperazine-1-carbonyl]- (commercial) and 5- N-methyl-4-(2,2,2-Methylsulfamoyl-2-(2,2,2-trifluoro- trifluoro-ethoxy)- ethoxy)-benzoicacid (compound 6.11) benzenesulfonamide 534 3-[4-(4-Cyano-2-fluoro-3-Fluoro-4-piperazin-1-yl- 501.1 phenyl)-piperazine-1- benzonitrile(WO9625414) and 5- carbonyl]-N-methyl-4-Methylsulfamoyl-2-(2,2,2-trifluoro- (2,2,2-trifluoro-ethoxy)-ethoxy)-benzoic acid (compound 6.11) benzenesulfonamide 5353-[4-(4-Acetyl-2-fluoro- 1-(3-Fluoro-4-piperazin-1-yl- 518.2phenyl)-piperazine-1- phenyl)-ethanone (WO9714690) andcarbonyl]-N-methyl-4- 5-Methylsulfamoyl-2-(2,2,2-(2,2,2-trifluoro-ethoxy)- trifluoro-ethoxy)-benzoic acidbenzenesulfonamide (compound 6.11) 536 3-[4-(2-Fluoro-4-1-(2-Fluoro-4-methanesulfonyl- 554.1 methanesulfonyl- phenyl)-piperazine(commercial) phenyl)-piperazine-1- and 5-Methylsulfamoyl-2-(2,2,2-carbonyl]-N-methyl-4- trifluoro-ethoxy)-benzoic acid(2,2,2-trifluoro-ethoxy)- (compound 6.11) benzenesulfonamide 537N-Methyl-4-(2,2,2- 1-(4-Trifluoromethyl-phenyl)- 526.0trifluoro-ethoxy)-3-[4- piperazine (commercial) and 5-(4-trifluoromethyl- Methylsulfamoyl-2-(2,2,2-trifluoro-phenyl)-piperazine-1- ethoxy)-benzoic acid (compound 6.11)carbonyl]-benzene sulfonamide 538 [4-(4-Ethanesulfonyl-2-1-(4-Ethanesulfonyl-2-fluoro- 513.3 fluoro-phenyl)- phenyl)-piperazine(compound 6.12) piperazin-1-yl]-(2- and 2-Isopropoxy-5- isopropoxy-5-methanesulfonyl-benzoic acid methanesulfonyl- (compound 1.2)phenyl)-methanone 539 {4-[4-(Butane-1-1-[4-(Butane-1-sulfonyl)-2-fluoro- 541.0 sulfonyl)-2-fluoro-phenyl]-piperazine (compound 6.13) phenyl]-piperazin-1-yl}- and2-Isopropoxy-5- (2-isopropoxy-5- methanesulfonyl-benzoic acidmethanesulfonyl- (compound 1.2) phenyl)-methanone 540 4-[4-(5-3-Fluoro-4-piperazin-1-yl- 472.3 Cyclopropanesulfonyl-2- benzonitrile(WO9625414) and 5- isopropoxy-benzoyl)-Cyclopropanesulfonyl-2-isopropoxy- piperazin-1-yl]-3-fluoro- benzoicacid (compound 6.14) benzonitrile 541 (5-Cyclopropane1-(2-Fluoro-4-trifluoromethyl-phenyl)- 515.4 sulfonyl-2-isopropoxy-piperazine (compound 1.1) and 5- phenyl)-[4-(2-fluoro-4-Cyclopropanesulfonyl-2-isopropoxy- trifluoro methyl-phenyl)- benzoicacid (compound 6.14) piperazin-1-yl]-methanone 542(5-Cyclopropanesulfonyl- 1-(2-Fluoro-4-methanesulfonyl- 539.52-isobutoxy- phenyl)-piperazine (commercial) phenyl)-[4-(2-fluoro-4- and5-Cyclopropanesulfonyl-2- methane sulfonyl- isobutoxy-benzoic acid(compound 6.15) phenyl)-piperazin-1-yl]- methanone 5434-[4-(5-Cyclopropanesulfonyl- 3-Fluoro-4-piperazin-1-yl- 486.52-isobutoxy- benzonitrile (WO9625414) and 5- benzoyl)-piperazin-1-yl]-Cyclopropanesulfonyl-2-isobutoxy- 3-fluoro-benzonitrile benzoic acid(compound 6.15) 544 (5-Cyclopropanesulfonyl-1-(2-Fluoro-4-trifluoromethyl-phenyl)- 529.4 2-isobutoxy- piperazine(compound 1.1) and 5- phenyl)-[4-(2-fluoro-4-Cyclopropanesulfonyl-2-isobutoxy- trifluoromethyl-phenyl)- benzoic acid(compound 6.15) piperazin-1-yl]-methanone 545 (2-Cyclopentyloxy-5-1-(2-Fluoro-4-methanesulfonyl- 551.3 cyclopropanesulfonyl-phenyl)-piperazine (commercial) phenyl)-[4-(2-fluoro-4- and2-Cyclopentyloxy-5- methanesulfonyl- cyclopropanesulfonyl-benzoic acidphenyl)-piperazin-1-yl]- (compound 6.16) methanone 5464-[4-(2-Cyclopentyloxy- 3-Fluoro-4-piperazin-1-yl- 498.35-cyclopropanesulfonyl- benzonitrile (WO9625414) and 2-benzoyl)-piperazin-1-yl]- Cyclopentyloxy-5-cyclopropane3-fluoro-benzonitrile sulfonyl-benzoic acid (compound 6.16) 547(2-Cyclopentyloxy-5- 1-(2-Fluoro-4-trifluoromethyl-phenyl)- 541.3cyclopropanesulfonyl- piperazine (compound 1.1) and 2-phenyl)-[4-(2-fluoro-4- Cyclopentyloxy-5- trifluoromethyl-phenyl)-cyclopropanesulfonyl-benzoic acid piperazin-1-yl]-methanone (compound6.16) 548 (5-Cyclopropanesulfonyl- 1-(2-Fluoro-4-methanesulfonyl- 537.42-cyclopropylmethoxy- phenyl)-piperazine (commercial)phenyl)-[4-(2-fluoro-4- and 5-Cyclopropanesulfonyl-2-methanesulfonyl-phenyl)- cyclopropylmethoxy-benzoic acidpiperazin-1-yl]-methanone (compound 6.17) 5494-[4-(5-Cyclopropanesulfonyl- 3-Fluoro-4-piperazin-1-yl- 484.52-cyclopropylmethoxy- benzonitrile (WO9625414) and 5-benzoyl)-piperazin-1-yl]- Cyclopropanesulfonyl-2- 3-fluoro-benzonitrilecyclopropylmethoxy-benzoic acid (compound 6.17) 550(5-Cyclopropanesulfonyl- 1-(2-Fluoro-4-trifluoromethyl-phenyl)- 527.32-cyclopropylmethoxy- piperazine (compound 1.1) and 5- phenyl)-[4-(2-Cyclopropanesulfonyl-2- fluoro-4-trifluoromethyl-cyclopropylmethoxy-benzoic acid phenyl)-piperazin-1-yl]- (compound 6.17)methanone 551 (2-Cyclobutoxy-5- 1-(2-Fluoro-4-methanesulfonyl- 537.4cyclopropanesulfonyl- phenyl)-piperazine (commercial)phenyl)-[4-(2-fluoro-4- and 2-Cyclobutoxy-5- methanesulfonyl-cyclopropanesulfonyl-benzoic acid phenyl)-piperazin-1-yl]- (compound6.18) methanone 552 (5-Cyclopropanesulfonyl-1-(2-Fluoro-4-methanesulfonyl- 525.3 2-isopropoxy- phenyl)-piperazine(commercial) phenyl)-[4-(2-fluoro-4- and 5-Cyclopropanesulfonyl-2-methanesulfonyl- isopropoxy-benzoic acid phenyl)-piperazin-1-yl]-(compound 6.14) methanone 553 rac-3-[4-(2-Fluoro-4-1-(2-Fluoro-4-methanesulfonyl- 585.1 methanesulfonyl- phenyl)-piperazine(commercial) (M + NH4+) phenyl)-piperazine-1- andrac-5-Methylsulfamoyl-2-(2,2,2- carbonyl]-N-methyl-4-trifluoro-1-methyl-ethoxy)-benzoic (2,2,2-trifluoro-1- acid (compound6.19) methyl-ethoxy)- benzenesulfonamide 554 rac-N-Methyl-4-(2,2,2-1-(4-Trifluoromethyl-phenyl)- 557.2 trifluoro-1-methyl- piperazine(commercial) and rac-5- (M + NH4+) ethoxy)-3-[4-(4-Methylsulfamoyl-2-(2,2,2-trifluoro- trifluoromethyl-phenyl)-1-methyl-ethoxy)-benzoic acid piperazine-1-carbonyl]- (compound 6.19)benzenesulfonamide 555 rac-3-[4-(4-Cyano-2- 3-Fluoro-4-piperazin-1-yl-532.3 fluoro-phenyl)- benzonitrile (WO9625414) and rac- (M + NH4+)piperazine-1-carbonyl]- 5-Methylsulfamoyl-2-(2,2,2- N-methyl-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoic trifluoro-1-methyl- acid (compound6.19) ethoxy)-benzene sulfonamide 556 [4-(4-Cyclopropane1-(4-Cyclopropanesulfonyl-2-fluoro- 542.2 sulfonyl-2-fluoro-phenyl)-piperazine (compound 6.20) (M + NH4+) phenyl)-piperazin-1-yl]-and 2-Isopropoxy-5-methanesulfonyl- (2-isopropoxy-5- benzoic acid(compound 1.2) methanesulfonyl- phenyl)-methanone 557rac-3-[4-(4-Cyano-2,5- 2,5-Difluoro-4-piperazin-1-yl- 550.1difluoro-phenyl)- benzonitrile-trifluoro-acetic acid (M + NH4+)piperazine-1-carbonyl]- (compound 2.8) and rac-5- N-methyl-4-(2,2,2-Methylsulfamoyl-2-(2,2,2-trifluoro- trifluoro-1-methyl-ethoxy)-1-methyl-ethoxy)-benzoic acid benzene sulfonamide (compound 6.19) 558rac-3-[4-(4-Cyano-2,3- 2,3-Difluoro-4-piperazin-1-yl- 550.1difluoro-phenyl)- benzonitrile-trifluoro-acetic acid (M + NH4+)piperazine-1-carbonyl]- (compound 2.7) and rac-5- N-methyl-4-(2,2,2-Methylsulfamoyl-2-(2,2,2-trifluoro- trifluoro-1-methyl-ethoxy)-1-methyl-ethoxy)-benzoic acid benzene sulfonamide (compound 6.19) 559{4-[2-Fluoro-4- 1-[2-Fluoro-4-(propane-2-sulfonyl)- 544.3(propane-2-sulfonyl)- phenyl]-piperazine (compound 6.21) (M + NH4+)phenyl]-piperazin-1-yl} and 2-Isopropoxy-5-methanesulfonyl-(2-isopropoxy-5- benzoic acid (compound 1.2) methanesulfonyl-phenyl)-methanone 560 [4-(4- 1-(4-Cyclopropylmethanesulfonyl-2- 556.2Cyclopropylmethanesulfonyl- fluoro-phenyl)-piperazine (M + NH4+)2-fluoro-phenyl)- (compound 6.22) and 2-Isopropoxy- piperazin-1-yl]-(2-5-methanesulfonyl-benzoic acid isopropoxy-5- (compound 1.2)methanesulfonyl- phenyl)-methanone 561 {4-[2-Fluoro-4-(2-methoxy-1-[2-Fluoro-4-(2-methoxy- 560.3 ethanesulfonyl)-phenyl]-ethanesulfonyl)-phenyl]-piperazine (M + NH4+) piperazin-1-yl}-(2-(compound 6.23) and 2-Isopropoxy- isopropoxy-5-5-methanesulfonyl-benzoic acid methanesulfonyl- (compound 1.2)phenyl)-methanone 562 (2-Cyclopropylmethoxy-1-(4-Ethanesulfonyl-2-fluoro- 542.2 5-methanesulfonyl-phenyl)-piperazine (compound 6.12) (M + NH4+) phenyl)-[4-(4- and2-Cyclopropylmethoxy-5- ethanesulfonyl-2-fluoro- methanesulfonyl-benzoicacid phenyl)-piperazin-1-yl]- (compound 1.4) methanone 563(2-Cyclopentyloxy-5- 1-(4-Ethanesulfonyl-2-fluoro- 556.1methanesulfonyl- phenyl)-piperazine (compound 6.12) (M + NH4+)phenyl)-[4-(4- and 2-Cyclopentyloxy-5- ethanesulfonyl-2-fluoro-methanesulfonyl-benzoic acid phenyl)-piperazin-1-yl]- (compound 1.6)methanone 564 (2-Cyclohexyloxy-5- 1-(4-Ethanesulfonyl-2-fluoro- 570.2methanesulfonyl- phenyl)-piperazine (compound 6.12) (M + NH4+)phenyl)-[4-(4- and 2-Cyclohexyloxy-5- ethanesulfonyl-2-fluoro-methanesulfonyl-benzoic acid phenyl)-piperazin-1-yl]- (compound 3.2)methanone 565 [2-(2,2-Dimethyl- 1-(4-Ethanesulfonyl-2-fluoro- 558.2 (M +NH4+) propoxy)-5- phenyl)-piperazine (compound 6.12) methanesulfonyl-and 2-(2,2-Dimethyl-propoxy)-5- phenyl]-[4-(4- methanesulfonyl-benzoicacid ethanesulfonyl-2-fluoro- (compound 3.3) phenyl)-piperazin-1-yl]-methanone 566 [4-(4-Ethanesulfonyl-2- 1-(4-Ethanesulfonyl-2-fluoro-544.2 (M + NH4+) fluoro-phenyl)- phenyl)-piperazine (compound 6.12)piperazin-1-yl]-(2- and 2-Isobutoxy-5-methanesulfonyl- isobutoxy-5-benzoic acid (compound 1.3) methanesulfonyl- phenyl)-methanone 567(2-Cyclobutoxy-5- 1-(4-Ethanesulfonyl-2-fluoro- 542.3 methanesulfonyl-phenyl)-piperazine (compound 6.12) (M + NH4+) phenyl)-[4-(4- and2-Cyclobutoxy-5- ethanesulfonyl-2-fluoro- methanesulfonyl-benzoic acidphenyl)-piperazin-1-yl]- (compound 3.4) methanone 568rac-(2-sec-Butoxy-5- 1-(4-Ethanesulfonyl-2-fluoro- 544.2methanesulfonyl- phenyl)-piperazine (compound 6.12) (M + NH4+)phenyl)-[4-(4- and rac-2-sec-Butoxy-5- ethanesulfonyl-2-fluoro-methanesulfonyl-benzoic acid phenyl)-piperazin-1-yl]- (compound 3.5)methanone 569 (2-Cyclobutylmethoxy-5- 1-(4-Ethanesulfonyl-2-fluoro-556.1 methanesulfonyl- phenyl)-piperazine (compound 6.12) (M + NH4+)phenyl)-[4-(4- and 2-Cyclobutylmethoxy-5- ethanesulfonyl-2-fluoro-methanesulfonyl-benzoic acid phenyl)-piperazin-1-yl]- (compound 2.12)methanone 570 [4-(4-Cyclobutanesulfonyl-1-(4-Cyclobutanesulfonyl-2-fluoro- 556.1 2-fluoro-phenyl)-piperazin-phenyl)-piperazine hydrochloride (M + NH4+) 1-yl]-(2-isopropoxy-(compound 6.24) and 2-Isopropoxy- 5-methanesulfonyl-5-methanesulfonyl-benzoic acid phenyl)-methanone (compound 1.2) 571[4-(4-Cyclopentanesulfonyl-2- 1-(4-Cyclopentanesulfonyl-2-fluoro- 570.3fluoro-phenyl)-piperazin-1-yl]- phenyl)-piperazine hydrochloride (M +NH4+) (2-isopropoxy-5- (compound 6.25) and 2-Isopropoxy-methanesulfonyl- 5-methanesulfonyl-benzoic acid phenyl)-methanone(compound 1.2) 572 [4-(4-Cyclopropane1-(4-Cyclopropanesulfonyl-2-fluoro- 537.2 sulfonyl-2-fluoro-phenyl)-piperazine (compound 6.20) phenyl)-piperazin-1-yl]- and2-Cyclopropylmethoxy-5- (2-cyclopropylmethoxy- methanesulfonyl-benzoicacid 5-methanesulfonyl- (compound 1.4) phenyl)-methanone 573(2-Cyclopentyloxy-5- 1-(4-Cyclopropanesulfonyl-2-fluoro- 568.0methanesulfonyl- phenyl)-piperazine (compound 6.20) (M + NH4+)phenyl)-[4-(4- and 2-Cyclopentyloxy-5- cyclopropanesulfonyl-2-methanesulfonyl-benzoic acid fluoro-phenyl)- (compound 1.6)piperazin-1-yl]-methanone 574 (2-Cyclohexyloxy-5-1-(4-Cyclopropanesulfonyl-2-fluoro- 582.1 methanesulfonyl-phenyl)-piperazine (compound 6.20) (M + NH4+) phenyl)-[4-(4- and2-Cyclohexyloxy-5-methanesulfonyl- cyclopropanesulfonyl-2- benzoic acid(compound 3.2) fluoro-phenyl)- piperazin-1-yl]-methanone 575[4-(4-Cyclopropanesulfonyl- 1-(4-Cyclopropanesulfonyl-2-fluoro- 570.22-fluoro- phenyl)-piperazine (compound 6.20) (M + NH4+)phenyl)-piperazin-1-yl]- and 2-(2,2-Dimethyl-propoxy)-5-[2-(2,2-dimethyl- methanesulfonyl-benzoic acid propoxy)-5- (compound3.3) methanesulfonyl- phenyl]-methanone 576 (2-Cyclobutoxy-5-1-(4-Cyclopropanesulfonyl-2-fluoro- 536.9 methanesulfonyl-phenyl)-piperazine (compound 6.20) phenyl)-[4-(4- and2-Cyclobutoxy-5-methane cyclopropanesulfonyl-2- sulfonyl-benzoic acid(compound 3.4) fluoro-phenyl)- piperazin-1-yl]- methanone 577{4-[2-Fluoro-4-(3,3,3- 1-[2-Fluoro-4-(3,3,3-trifluoro- 581.0trifluoro-propane-1- propane-1-sulfonyl)-phenyl]- sulfonyl)-phenyl]-piperazine (compound 6.26) and 2- piperazin-1-yl}-(2-Isopropoxy-5-methanesulfonyl- isopropoxy-5- benzoic acid (compound 1.2)methanesulfonyl- phenyl)-methanone 578 [4-(4-Cyclopropane1-(4-Cyclopropanesulfonyl-2-fluoro- 556.1 sulfonyl-2-fluoro-phenyl)-piperazine (compound 6.20) (M + NH4+) phenyl)-piperazin-1-yl]-and 2-Isobutoxy-5-methanesulfonyl- (2-isobutoxy-5- benzoic acid(compound 1.3) methanesulfonyl- phenyl)-methanone 579 {4-[2-Fluoro-4-1-[2-Fluoro-4-(tetrahydro-pyran-4- 586.2 (tetrahydro-pyran-4-sulfonyl)-phenyl]-piperazine (M + NH4+) sulfonyl)-phenyl]- (compound6.27) and 2- piperazin-1-yl}-(2- Isopropoxy-5-methanesulfonyl-isopropoxy-5- benzoic acid (compound 1.2) methanesulfonyl-phenyl)-methanone 580 (2-tert-Butoxy-5-1-[2-Fluoro-4-(propane-2-sulfonyl)- 558.2 methanesulfonyl-phenyl]-piperazine (compound 6.21) (M + NH4+) phenyl)-{4-[2-fluoro-4-and 2-tert-Butoxy-5-methane (propane-2-sulfonyl)- sulfonyl-benzoic acid(compound 2.19) phenyl]-piperazin-1-yl-}- methanone 581(2-tert-Butoxy-5- 1-(4-Ethanesulfonyl-2-fluoro- 544.2 methanesulfonyl-phenyl)-piperazine (compound 6.12) (M + NH4+) phenyl)-[4-(4- and2-tert-Butoxy-5-methane ethanesulfonyl-2-fluoro- sulfonyl-benzoic acid(compound 2.19) phenyl)-piperazin-1-yl]- methanone 582 (2-tert-Butoxy-5-1-(4-Cyclopropanesulfonyl-2-fluoro- 556.1 methanesulfonyl-phenyl)-piperazine (compound 6.20) (M + NH4+) phenyl)-[4-(4- and2-tert-Butoxy-5-methane cyclopropanesulfonyl-2- sulfonyl-benzoic acid(compound 2.19) fluoro-phenyl)- piperazin-1-yl]-methanone 583{4-[2-Fluoro-4- 1-[2-Fluoro-4-(propane-2-sulfonyl)- 584.1(propane-2-sulfonyl)- phenyl]-piperazine (compound 6.21) (M + NH4+)phenyl]-piperazin-1-yl}- and 5-Methanesulfonyl-2-(2,2,2-[5-methanesulfonyl-2- trifluoro-ethoxy)-benzoic acid(2,2,2-trifluoro-ethoxy)- (compound 1.5) phenyl]-methanone 584[4-(4-Ethanesulfonyl-2- 1-(4-Ethanesulfonyl-2-fluoro- 570.3fluoro-phenyl)- phenyl)-piperazine (compound 6.12) (M + NH4+)piperazin-1-yl]-[5- and 5-Methanesulfonyl-2-(2,2,2- methanesulfonyl-2-trifluoro-ethoxy)-benzoic acid (2,2,2-trifluoro-ethoxy)- (compound 1.5)phenyl]-methanone 585 [4-(4-Cyclopropanesulfonyl-1-(4-Cyclopropanesulfonyl-2-fluoro- 582.1 2-fluoro- phenyl)-piperazine(compound 6.20) (M + NH4+) phenyl)-piperazin-1-yl]- and5-Methanesulfonyl-2-(2,2,2- [5-methanesulfonyl-2-trifluoro-ethoxy)-benzoic acid (2,2,2-trifluoro-ethoxy)- (compound 1.5)phenyl]-methanone 586 rac{4-[2-Fluoro-4-1-[2-Fluoro-4-(propane-2-sulfonyl)- 598.2 (propane-2-sulfonyl)-phenyl]-piperazine (compound 6.21) (M + NH4+) phenyl]-piperazin-1-yl}-and rac-5-Methanesulfonyl-2-(2,2,2- [5-methanesulfonyl-2-trifluoro-1-methyl-ethoxy)-benzoic (2,2,2-trifluoro-1- acid (compound3.1) methyl-ethoxy)-phenyl]- methanone 587 rac-[4-(4-Ethanesulfonyl-1-(4-Ethanesulfonyl-2-fluoro- 584.1 2-fluoro-phenyl)-piperazin-phenyl)-piperazine (compound 6.12) (M + NH4+)1-yl]-[5-methanesulfonyl-2- and rac-5-Methanesulfonyl-2-(2,2,2-(2,2,2-trifluoro-1- trifluoro-1-methyl-ethoxy)-benzoicmethyl-ethoxy)-phenyl]- acid (compound 3.1) methanone 588rac-[4-(4-Cyclopropanesulfonyl- 1-(4-Cyclopropanesulfonyl-2-fluoro-596.2 2-fluoro-phenyl)-piperazin- phenyl)-piperazine (compound 6.20)(M + NH4+) 1-yl]-[5-methanesulfonyl-2- andrac-5-Methanesulfonyl-2-(2,2,2- (2,2,2-trifluoro-1-trifluoro-1-methyl-ethoxy)-benzoic methyl-ethoxy)-phenyl]- acid(compound 3.1) methanone 589 [4-(4-Cyclohexanesulfonyl-1-(4-Cyclohexanesulfonyl-2-fluoro- 584.3 2-fluoro-phenyl)-piperazin-phenyl)-piperazine (compound 6.28) (M + NH4+) 1-yl]-(2-isopropoxy-5- and2-Isopropoxy-5-methanesulfonyl- methanesulfonyl- benzoic acid (compound1.2) phenyl)-methanone 590 {4-[2,3-Difluoro-4-1-[2,3-Difluoro-4-(propane-2- 545.2 (propane-2-sulfonyl)-sulfonyl)-phenyl]-piperazine phenyl]-piperazin-1-yl}- hydrochloride(compound 6.29) and (2-isopropoxy-5- 2-Isopropoxy-5-methanesulfonyl-methanesulfonyl- benzoic acid (compound 1.2) phenyl)-methanone 591[4-(4-Ethanesulfonyl- 1-(4-Ethanesulfonyl-2,3-difluoro- 531.12,3-difluoro-phenyl)- phenyl)-piperazine hydrochloridepiperazin-1-yl]-(2- (compound 6.30) and 2-Isopropoxy- isopropoxy-5-5-methanesulfonyl-benzoic acid methanesulfonyl- (compound 1.2)phenyl)-methanone 592 [4-(4-Cyclopropanesulfonyl-1-(4-Cyclopropanesulfonyl-2,3- 543.3 2,3-difluoro-difluoro-phenyl)-piperazine phenyl)-piperazin-1-yl]- hydrochloride(compound 6.31) and (2-isopropoxy-5- 2-Isopropoxy-5-methanesulfonyl-methanesulfonyl- benzoic acid (compound 1.2) phenyl)-methanone 593{4-[2,5-Difluoro-4- 1-[2,5-Difluoro-4-(propane-2- 545.2(propane-2-sulfonyl)- sulfonyl)-phenyl]-piperazinephenyl]-piperazin-1-yl}- hydrochloride (compound 6.32) and(2-isopropoxy-5- 2-Isopropoxy-5-methanesulfonyl- methanesulfonyl-benzoic acid (compound 1.2) phenyl)-methanone 594 [4-(4-Ethanesulfonyl-1-(4-Ethanesulfonyl-2,5-difluoro- 531.1 2,5-difluoro-phenyl)-phenyl)-piperazine hydrochloride piperazin-1-yl]-(2- (compound 6.33) and2-Isopropoxy- isopropoxy-5- 5-methanesulfonyl-benzoic acidmethanesulfonyl- (compound 1.2) phenyl)-methanone 595[4-(4-Cyclopropanesulfonyl- 1-(4-Cyclopropanesulfonyl-2,5- 543.32,5-difluoro- difluoro-phenyl)-piperazine phenyl)-piperazin-1-yl]-hydrochloride (compound 6.34) and (2-isopropoxy-5-2-Isopropoxy-5-methanesulfonyl- methanesulfonyl- benzoic acid (compound1.2) phenyl)-methanone 596 (2-tert-Butoxy-5-1-(4-Cyclobutanesulfonyl-2-fluoro- 553.6 methanesulfonyl-phenyl)-piperazine hydrochloride phenyl)-[4-(4- (compound 6.24) and2-tert-Butoxy- cyclobutanesulfonyl-2- 5-methanesulfonyl-benzoic acidfluoro-phenyl)- (compound 2.19) piperazin-1-yl]-methanone 597(2-tert-Butoxy-5- 1-[2,3-Difluoro-4-(propane-2- 503.1 methanesulfonyl-sulfonyl)-phenyl]-piperazine (M-tBu + H) phenyl)-{4-[2,3-difluoro-hydrochloride (compound 6.29) and 4-(propane-2-sulfonyl)-2-tert-Butoxy-5-methanesulfonyl- phenyl]-piperazin-1-yl}- benzoic acid(compound 2.19) methanone 598 (2-tert-Butoxy-5-1-(4-Ethanesulfonyl-2,3-difluoro- 489.2 methanesulfonyl-phenyl)-piperazine hydrochloride (M-tBu + H) phenyl)-[4-(4- (compound6.30) and 2-tert-Butoxy- ethanesulfonyl-2,3- 5-methanesulfonyl-benzoicacid difluoro-phenyl)- (compound 2.19) piperazin-1-yl]-methanone 599(2-tert-Butoxy-5- 1-(4-Cyclopropanesulfonyl-2,3- 501.1 methanesulfonyl-difluoro-phenyl)-piperazine (M-tBu + H) phenyl)-[4-(4- hydrochloride(compound 6.31) and cyclopropanesulfonyl-2-tert-Butoxy-5-methanesulfonyl- 2,3-difluoro-phenyl)- benzoic acid(compound 2.19) piperazin-1-yl]-methanone 600 (2-tert-Butoxy-5-1-[2,5-Difluoro-4-(propane-2- 503.2 methanesulfonyl-sulfonyl)-phenyl]-piperazine (M-tBu + H) phenyl)-{4-[2,5-difluoro-hydrochloride (compound 6.32) and 4-(propane-2-sulfonyl)-2-tert-Butoxy-5-methanesulfonyl- phenyl]-piperazin-1-yl}- benzoic acid(compound 2.19) methanone 601 (2-tert-Butoxy-5-1-(4-Ethanesulfonyl-2,5-difluoro- 489.1 methanesulfonyl-phenyl)-piperazine hydrochloride (M-tBu + H) phenyl)-[4-(4- (compound6.33) and 2-tert-Butoxy- ethanesulfonyl-2,5- 5-methanesulfonyl-benzoicacid difluoro-phenyl)- (compound 2.19) piperazin-1-yl]-methanone 602(2-tert-Butoxy-5- 1-(4-Cyclopropanesulfonyl-2,5- 501.3 methanesulfonyl-difluoro-phenyl)-piperazine (M-tBu + H) phenyl)-[4-(4- hydrochloride(compound 6.34) and cyclopropanesulfonyl-2-tert-Butoxy-5-methanesulfonyl- 2,5-difluoro-phenyl)- benzoic acid(compound 2.19) piperazin-1-yl]-methanone 603 [4-(4-Cyclobutanesulfonyl-1-(4-Cyclobutanesulfonyl-2-fluoro- 579.1 2-fluoro- phenyl)-piperazinehydrochloride phenyl)-piperazin-1-yl]- (compound 6.24) and 5-[5-methanesulfonyl-2- Methanesulfonyl-2-(2,2,2-trifluoro-(2,2,2-trifluoro-ethoxy)- ethoxy)-benzoic acid (compound 1.5)phenyl]-methanone 604 {4-[2,3-Difluoro-4- 1-[2,3-Difluoro-4-(propane-2-602.2 (propane-2-sulfonyl)- sulfonyl)-phenyl]-piperazine (M + NH4+)phenyl]-piperazin-1-yl}- hydrochloride (compound 6.29) and[5-methanesulfonyl-2- 5-Methanesulfonyl-2-(2,2,2-(2,2,2-trifluoro-ethoxy)- trifluoro-ethoxy)-benzoic acidphenyl]-methanone (compound 1.5) 605 [4-(4-Ethanesulfonyl-1-(4-Ethanesulfonyl-2,3-difluoro- 571.2 2,3-difluoro-phenyl)-phenyl)-piperazine hydrochloride piperazin-1-yl]-[5- (compound 6.30) and5- methanesulfonyl-2- Methanesulfonyl-2-(2,2,2-trifluoro-(2,2,2-trifluoro-ethoxy)- ethoxy)-benzoic acid (compound 1.5)phenyl]-methanone 606 [4-(4-Cyclopropanesulfonyl-1-(4-Cyclopropanesulfonyl-2,3- 600.2 2,3-difluoro-difluoro-phenyl)-piperazine (M + NH4+) phenyl)-piperazin-1-yl]-hydrochloride (compound 6.31) and [5-methanesulfonyl-2-5-Methanesulfonyl-2-(2,2,2- (2,2,2-trifluoro-ethoxy)-trifluoro-ethoxy)-benzoic acid phenyl]-methanone (compound 1.5) 607{4-[2,5-Difluoro-4- 1-[2,5-Difluoro-4-(propane-2- 602.3(propane-2-sulfonyl)- sulfonyl)-phenyl]-piperazine (M + NH4+)phenyl]-piperazin-1-yl}- hydrochloride (compound 6.32) and[5-methanesulfonyl-2- 5-Methanesulfonyl-2-(2,2,2-(2,2,2-trifluoro-ethoxy)- trifluoro-ethoxy)-benzoic acidphenyl]-methanone (compound 1.5) 608 [4-(4-Ethanesulfonyl-1-(4-Ethanesulfonyl-2,5-difluoro- 588.3 2,5-difluoro-phenyl)-phenyl)-piperazine hydrochloride (M + NH4+) piperazin-1-yl]-[5-(compound 6.33) and 5-Methanesulfonyl- methanesulfonyl-2-2-(2,2,2-trifluoro-ethoxy)- (2,2,2-trifluoro-ethoxy)- benzoic acid(compound 1.5) phenyl]-methanone 609 [4-(4-Cyclopropanesulfonyl-1-(4-Cyclopropanesulfonyl-2,5- 600.2 2,5-difluoro-difluoro-phenyl)-piperazine (M + NH4+) phenyl)-piperazin-1-yl]-hydrochloride (compound 6.34) and [5-methanesulfonyl-2-5-Methanesulfonyl-2-(2,2,2- (2,2,2-trifluoro-ethoxy)-trifluoro-ethoxy)-benzoic acid phenyl]-methanone (compound 1.5) 610rac-[4-(4-Cyclobutanesulfonyl- 1-(4-Cyclobutanesulfonyl-2-fluoro- 593.22-fluoro- phenyl)-piperazine hydrochloride phenyl)-piperazin-1-yl]-(compound 6.24) and rac-5- [5-methanesulfonyl-2-Methanesulfonyl-2-(2,2,2-trifluoro- (2,2,2-trifluoro-1-1-methyl-ethoxy)-benzoic acid methyl-ethoxy)-phenyl]- (compound 3.1)methanone 611 rac-{4-[2,3-Difluoro-4- 1-[2,3-Difluoro-4-(propane-2-599.2 (propane-2-sulfonyl)- sulfonyl)-phenyl]-piperazinephenyl]-piperazin-1-yl}- hydrochloride (compound 6.29) and[5-methanesulfonyl-2- rac-5-Methanesulfonyl-2-(2,2,2-(2,2,2-trifluoro-1- trifluoro-1-methyl-ethoxy)-benzoicmethyl-ethoxy)-phenyl]- acid (compound 3.1) methanone 612 rac-[4-(4-1-(4-Ethanesulfonyl-2,3-difluoro- 602.2 Ethanesulfonyl-2,3-phenyl)-piperazine hydrochloride (M + NH4+) difluoro-phenyl)- (compound6.30) and rac-5- piperazin-1-yl]-[5- Methanesulfonyl-2-(2,2,2-trifluoro-methanesulfonyl-2- 1-methyl-ethoxy)-benzoic acid (2,2,2-trifluoro-1-(compound 3.1) methyl-ethoxy)-phenyl]- methanone 613 rac-[4-(4-1-(4-Cyclopropanesulfonyl-2,3- 614.3(M + NH4+) Cyclopropanesulfonyl-difluoro-phenyl)-piperazine 2,3-difluoro-phenyl)- hydrochloride(compound 6.31) and piperazin-1-yl]-[5- rac-5-Methanesulfonyl-2-(2,2,2-methanesulfonyl-2- trifluoro-1-methyl-ethoxy)-benzoic(2,2,2-trifluoro-1- acid (compound 3.1) methyl-ethoxy)-phenyl]-methanone 614 rac-4-[2,5-Difluoro-4- 1-[2,5-Difluoro-4-(propane-2- 616.2(propane-2-sulfonyl)- sulfonyl)-phenyl]-piperazine (M + NH4+)phenyl]-piperazin-1-yl}- hydrochloride (compound 6.32) and[5-methanesulfonyl-2- rac-5-Methanesulfonyl-2-(2,2,2-(2,2,2-trifluoro-1- trifluoro-1-methyl-ethoxy)-benzoicmethyl-ethoxy)-phenyl]- acid (compound 3.1) methanone 615 rac-[4-(4-1-(4-Ethanesulfonyl-2,5-difluoro- 602.3 Ethanesulfonyl-2,5-phenyl)-piperazine hydrochloride (M + NH4+) difluoro-phenyl)- (compound6.33) and rac-5- piperazin-1-yl]-[5- Methanesulfonyl-2-(2,2,2-trifluoro-methanesulfonyl-2- 1-methyl-ethoxy)-benzoic acid (2,2,2-trifluoro-1-(compound 3.1) methyl-ethoxy)-phenyl]- methanone 616 rac-[4-(4-1-(4-Cyclopropanesulfonyl-2,5- 614.3 Cyclopropanesulfonyl-difluoro-phenyl)-piperazine (M + NH4+) 2,5-difluoro-phenyl)-hydrochloride (compound 6.34) and piperazin-1-yl]-[5-rac-5-Methanesulfonyl-2-(2,2,2- methanesulfonyl-2-trifluoro-1-methyl-ethoxy)-benzoic (2,2,2-trifluoro-1- acid (compound3.1) methyl-ethoxy)-phenyl]- methanone 617 [4-(4-Hydroxy-phenyl)-4-Piperazin-1-yl-phenol 419.1 piperazin-1-yl]-(2- (commercial) and2-Isopropoxy-5- isopropoxy-5- methanesulfonyl-benzoic acidmethanesulfonyl- (compound 1.2) phenyl)-methanone 618rac-(2-Isopropoxy-5- rac-2-Methyl-1-(4-trifluoromethyl- 485.2methanesulfonyl- phenyl)-piperazine hydrochloridephenyl)-[3-methyl-4-(4- (compound 6.35) and 2- trifluoromethyl-phenyl)-Isopropoxy-5-methanesulfonyl- piperazin-1-yl]-methanone benzoic acid(compound 1.2) 619 1-{4-Isopropoxy-3-[4-(4-1-(4-Trifluoromethyl-phenyl)- 435.2 trifluoromethyl-phenyl)- piperazine(commercial) and 5- piperazine-1-carbonyl]- Acetyl-2-isopropoxy-benzoicacid phenyl}-ethanone (compound 6.36)

EXAMPLE 6.37 Preparation of4-isopropoxy-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzoicacid

(a)4-Isopropoxy-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzonitrile

To a solution of 3.6 mmol 5-cyano-2-isopropoxy-benzoic acid (compound1.13) in 20 ml THF were added 4.0 mmol TBTU, 21.6 mmolN-ethyldiisopropylamine and 4.0 mmol1-(4-trifluoromethyl-phenyl)-piperazine (commercial). The reaction wasthen stirred at RT for 16 h, concentrated in vacuo, and purified bychromatography on silica gel (eluant: ethyl acetate/heptane 1:1) toafford the title compound. MS (m/e): 418.3 (M+H⁺, 100%)

(b)4-Isopropoxy-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzoicacid

To 3.2 mmol4-isopropoxy-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzonitrilein 15 ml ethanol was added 30 mmol 2 M aq NaOH and the mixture washeated at 85° C. for 16 h. The mixture was then cooled to RT, dilutedwith water and acidified to pH 1 with conc HCl, and then extracted threetimes with ethyl acetate. The combined organic phases were dried withNa₂SO₄, concentrated in vacuo, and the residue purified bychromatography on silica gel (eluant: methanol/dichloromethane 5:95) toafford the title compound. MS (m/e): 435.3 ([M−H]⁻, 100%)

EXAMPLE 620 Preparation of4-isopropoxy-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzoicacid methyl ester

To 0.3 mmol4-isopropoxy-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzoicacid in 2 ml DMF was added 0.4 mmol CDI, and the mixture heated at 50°C. for 30 min. 5.2 mmol methanol was then added, and the mixture wasstirred at RT for 16 h. The mixture was then cooled to room temperature,concentrated in vacuo, and the residue chromatographed on silica gel(eluant: ethyl acetate/heptane 1:4) to afford the title compound. MS(m/e): 451.2 (M+H⁺, 100%)

EXAMPLE 621 Preparation of4-isopropoxy-N-methyl-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzamide

To 0.3 mmol4-isopropoxy-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzoicacid in 2 ml DMF was added 0.4 mmol CDI, and the mixture heated at 50°C. for 30 min. 5.2 mmol methylamine (41% aq solution) was then added,and the mixture was stirred at RT for 16 h. The mixture was then cooledto room temperature, concentrated in vacuo, and the residuechromatographed on silica gel (eluant: ethyl acetate) to afford thetitle compound. MS (m/e): 450.1 (M+H⁺, 100%)

EXAMPLE 6.38 Preparation of3-[4-(4-Cyano-3-fluoro-phenyl)-piperazine-1-carbonyl]-4-hydroxy-benzenesulfonamide

(a) 2-Hydroxy-5-sulfamoyl-benzoic acid

Ammonia gas was bubbled through a solution of 107 mmol5-chlorosulfonyl-2-hydroxy-benzoic acid in 250 ml acetone at 0° C. for 2h. Argon gas was then bubbled through the reaction mixture for 1 h topurge excess ammonia. The mixture was then diluted with water, the pHadjusted to pH 14 by addition of 5 M aq NaOH solution, and the mixturewas then extracted with ether/ethyl acetate (1:1). The aqueous phase wasacidified with concentrated HCl, saturated with NaCl, and extractedtwice with THF. The combined THF extracts were dried with Na₂SO₄.Evaporation of the solvent in vacuo followed by drying of the residue byheating at 60° C. overnight in vacuo yielded the title compound.

MS (m/e): 216.1 ([M−H]⁻, 100%)

(b) 2-Hydroxy-5-sulfamoyl-benzoic acid methyl ester

To 62 mmol 2-hydroxy-5-sulfamoyl-benzoic acid in 80 ml THF was added 80mmol CDI and the mixture heated at 50° C. for 1 h. 616 mmol methanol wasthen added, and the mixture was heated at 50° C. for 16 h. The mixturewas then cooled to room temperature, concentrated in vacuo, and theresidue chromatographed on silica gel (eluant: dichloromethane/methanol20:1). The product containing fractions were concentrated in vacuo andthe residue suspended in ethyl acetate and washed with aq NaHCO3solution. The organic phase was dried with Na₂SO₄ and concentrated invacuo to afford the title compound. MS (m/e): 230.2 ([M−H]⁻, 100%)

(c) 2-(4-Methoxy-benzyloxy)-5-sulfamoyl-benzoic acid methyl ester

To 4.8 mmol 2-hydroxy-5-sulfamoyl-benzoic acid methyl ester, 5.2 mmol4-methoxybenzyl alcohol and 5.2 mmol triphenylphosphine in 8 ml THF wasadded 5.2 mmol di-tert-butyl azodicarboxylate, and the mixture wasstirred at RT for 2 h. The mixture was then concentrated in vacuo. Theresidue was chromatographed on silica gel (eluant: ethyl acetate/heptanegradient) to afford the title compound. MS (m/e): 350.2 ([M−H]⁻, 100%)

(d) 2-(4-Methoxy-benzyloxy)-5-sulfamoyl-benzoic acid

To 2.5 mmol 2-(4-methoxy-benzyloxy)-5-sulfamoyl-benzoic acid methylester in 6 ml THF was added 5 mmol 2 M aq NaOH, and the mixture washeated at 60° C. for 30 min. The mixture was then cooled to RT andextracted twice with ethyl acetate. The aqueous phase was acidified topH 1 with 5 M aq HCl and extracted with ethyl acetate. The combinedorganic phases were washed with saturated aq NaCl and dried with Na₂SO₄.Evaporation in vacuo afforded the title compound. MS (m/e): 336.1([M−H]⁻, 100%)

(e)(3-[4-(4-Cyano-3-fluoro-phenyl)-piperazine-1-carbonyl]-4-(4-methoxy-benzyloxy)-benzenesulfonamide

To a solution of 3.5 mmol 2-(4-methoxy-benzyloxy)-5-sulfamoyl-benzoicacid in 4 ml dimethylformamide and 12 ml THF were added 5.3 mmol TBTU,17.5 mmol N-ethyldiisopropylamine and 3.5 mmol3-fluoro-4-piperazin-1-yl-benzonitrile (WO9625414). The reaction wasthen stirred at RT for 1 h, concentrated in vacuo, and purified bychromatography on silica gel (eluant: ethyl acetate/heptane gradient) toafford the title compound. MS (m/e): 525.1 (M+H⁺)

(f)(3-[4-(4-Cyano-3-fluoro-phenyl)-piperazine-1-carbonyl]-4-hydroxy-benzenesulfonamide

Hydrogen gas was bubbled through a solution of 1.0 mmol(3-[4-(4-Cyano-3-fluoro-phenyl)-piperazine-1-carbonyl]-4-(4-methoxy-benzyloxy)-benzenesulfonamidein 40 ml THF containing 50 mg 10% palladioum on charcoal and a few dropsof acetic acid for 6 h at RT. The reaction mixture was then purged withargon, filtered through celite, and the filtrate was concentrated invacuo. The residue was purified by chromatography on silica gel (eluant:methanol/dichloromethane gradient) to afford the title compound. MS(m/e): 403.1 ([M−H]⁻, 100%)

In analogy to Example 6.38(e) and (f), compounds 6.39 and 6.40 of thefollowing table were prepared from2-(4-methoxy-benzyloxy)-5-sulfamoyl-benzoic acid and the appropriatepiperazine, followed by hydrogenolysis with catalytic palladium oncharcoal:

Expl. MS No name piperazine (m/e) 6.39 3-[4-(4-Cyano-2-fluoro-3-Fluoro-4-piperazin- 403.1 phenyl)-piperazine-1- 1-yl-benzonitrile (M −H) carbonyl]-4-hydroxy- (WO9625414) benzenesulfonamide 6.403-[4-(2-Fluoro-4- 1-(2-Fluoro-4- 456.2 methanesulfonyl-phenyl)-methanesulfonyl- (M − H) piperazine-1-carbonyl]-4- phenyl)-piperazinehydroxy-benzenesulfonamide (commercial)

EXAMPLE 622 Preparation of3-[4-(4-cyano-3-fluoro-phenyl)-piperazine-1-carbonyl]-4-isobutoxy-benzenesulfonamide

To 0.1 mmol(3-[4-(4-cyano-3-fluoro-phenyl)-piperazine-1-carbonyl]-4-hydroxybenzenesulfonamide (compound 6.38), 0.5 mmol 2-methyl-1-propanol and 0.3mmol diphenyl-2-pyridylphosphine in 4 ml THF was added 0.3 mmoldi-tert-butyl azodicarboxylate, and the mixture was stirred at 60° C.for 4 h. The mixture was then diluted with ethyl acetate and washedtwice with 5 M aq HCl and then with saturated aq NaCl solution. Theorganic phase was then dried with Na₂SO₄, and concentrated in vacuo. Theresidue was triturated in ether to afford the title compound. MS (m/e):459.2 ([M−H]⁻, 100%)

In analogy to Example 622, compounds 623 to 632 of the following tablewere prepared from compounds 6.38 to 6.40 and the appropriate alcohol:

MW Expl. found No. name Starting materials (MH⁺) 623 3-[4-(4-Cyano-3-3-[4-(4-Cyano-3-fluoro- 471.3 fluoro-phenyl)- phenyl)-piperazine-1- (M −H) piperazine-1-carbonyl]- carbonyl]-4-hydroxy- 4-cyclopentyloxy-benzenesulfonamide benzenesulfonamide (compound 6.38) and cyclopentanol624 3-[4-(4-Cyano-2- 3-[4-(4-Cyano-2-fluoro- 445.2 fluoro-phenyl)-phenyl)-piperazine-1- (M − H) piperazine-1-carbonyl]-carbonyl]-4-hydroxy- 4-isopropoxy- benzenesulfonamide benzenesulfonamide(compound 6.39) and 2- propanol 625 3-[4-(4-Cyano-2-3-[4-(4-Cyano-2-fluoro- 459.2 fluoro-phenyl)- phenyl)-piperazine-1- (M −H) piperazine-1-carbonyl]- carbonyl]-4-hydroxy- 4-isobutoxy-benzenesulfonamide benzenesulfonamide (compound 6.39) and2-methyl-1-propanol 626 3-[4-(4-Cyano-2- 3-[4-(4-Cyano-2-fluoro- 471.3fluoro-phenyl)- phenyl)-piperazine-1- (M − H) piperazine-1-carbonyl]-carbonyl]-4-hydroxy- 4-cyclopentyloxy- benzenesulfonamidebenzenesulfonamide (compound 6.39) and cyclopentanol 6273-[4-(2-Fluoro-4- 3-[4-(2-Fluoro-4- 512.3 methanesulfonyl-methanesulfonyl-phenyl)- (M − H) phenyl)-piperazine-1- piperazine-1-carbonyl]-4-isobutoxy- carbonyl]-4-hydroxy- benzenesulfonamidebenzenesulfonamide (compound 6.40) and 2-methyl-1-propanol 6284-Cyclopentyloxy-3-[4- 3-[4-(2-Fluoro-4- 524.5 (2-fluoro-4-methanesulfonyl-phenyl)- (M − H) methanesulfonyl- piperazine-1-phenyl)-piperazine-1- carbonyl]-4-hydroxy- carbonyl]- benzenesulfonamidebenzenesulfonamide (compound 6.40) and cyclopentanol 6293-[4-(4-Cyano-3- 3-[4-(4-Cyano-3-fluoro- 445.1 fluoro-phenyl)-phenyl)-piperazine-1- (M − H) piperazine-1-carbonyl]-carbonyl]-4-hydroxy- 4-isopropoxy- benzenesulfonamide benzenesulfonamide(compound 6.38) and 2- propanol 630 3-[4-(4-Cyano-3-3-[4-(4-Cyano-3-fluoro- 471.3 fluoro-phenyl)- phenyl)-piperazine-1- (M −H) piperazine-1-carbonyl]- carbonyl]-4-hydroxy- 4-cyclobutylmethoxy-benzenesulfonamide benzenesulfonamide (compound 6.38) andcyclobutanemethanol 631 3-[4-(2-Fluoro-4- 3-[4-(2-Fluoro-4- 498.4methanesulfonyl- methanesulfonyl-phenyl)- (M − H) phenyl)-piperazine-1-piperazine-1- carbonyl]-4- carbonyl]-4-hydroxy- isopropoxy-benzenesulfonamide benzenesulfonamide (compound 6.40) and 2- propanol632 4-Cyclobutylmethoxy- 3-[4-(2-Fluoro-4- 524.5 3-[4-(2-fluoro-4-methanesulfonyl-phenyl)- (M − H) methanesulfonyl- piperazine-1-phenyl)-piperazine-1- carbonyl]-4-hydroxy- carbonyl]- benzenesulfonamidebenzenesulfonamide (compound 6.40) and cyclobutanemethanol

EXAMPLE 7.1 Preparation of 3-Piperazin-1-yl-5-trifluoromethyl-pyridazine

(a)-3-Chloro-5-trifluoromethyl-pyridazine

5-Trifluoromethyl-pyridazin-3-ol [244268-34-6 (1 g) was added to astirred solution of phosphoryloxychloride, and the reaction mixture wasstirred at 80° C. for 1 hour. After such time, the reaction mixture wasallowed to cool to room temperature, poured onto ice and after 5 minuteswas extracted twice from the aqueous solution with dichloromethane. Thecombined organic phases were dried with sodium sulfate and concentratedin vacuo. The residue was distilled in a Kugelrohr apparatus (bp=80-100°C. @ 12 mBar) to yield the title compound (0.26 g). MS (m/e): 182.0

(b) 4-(5-Trifluoromethyl-pyridazin-3-yl)-piperazine-1-carboxylic acidtert-butyl ester

3-Chloro-5-trifluoromethyl-pyridazine (200 mg) was added topiperazine-1-carboxylic acid tert-butyl ester (231 mg) indimethylacetamide (3 mL), and the reaction mixture was stirred at 100°C. for 3 hours. After such time, the reaction mixture was allowed tocool down to room temperature and diluted with ethyl acetate. The solidwas filtered off and washed with ethyl acetate. The filtrate was thenconcentrated in vacuo and then purified by column chromatography (SiO₂,Heptane/EtOAc) to yield the title compound as a white solid (364 mg). MS(m/e): 333.4 (M+H⁺, 100%)

(c) 3-Piperazin-1-yl-5-trifluoromethyl-pyridazine

4-(5-Trifluoromethyl-pyridazin-3-yl)-piperazine-1-carboxylic acidtert-butyl ester (45 mg) was dissolved in dichloromethane (0.5 mL), andtrifluoroacetic acid was added (0.5 mL). The reaction mixture wasstirred for 30 minutes before being concentrated in vacuo to afford thecrude title compound which was used directly in the next step withoutfurther purification or analysis.

EXAMPLE 7.2 Preparation of5-Methanesulfonyl-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-benzoic acid

To 2-Fluoro-5-methanesulfonyl-benzoic acid (247569-56-8) (600 mg) indimethylacetamide (10 mL) was added cesium carbonate at 170° C.2-trifluoromethyl-propanol (0.94 mL) was first added to the reactionmixture followed by additionally 0.47 mL every 24 hours. After a totalof 72 hours, the reaction mixture was acidified by addition of formicacid, concentrated in vacuo and purified by preparative HPLC to yieldthe title compound as a light brown solid (897 mg). MS (m/e): 325.3.(M−H, 100%)

EXAMPLE 7.3 Preparation of 5-Methanesulfonyl-2-piperazin-1-yl-pyrimidine

(a) 3-Dimethylamino-2-methanesulfonyl-allylidene-dimethyl-ammonium;chloride

To sulfonyl-acetic acid (1.5 g) in dimethylformamide was slowly addedphosphorus oxychloride over 5 minutes, and the reaction was then stirredat 70° C. for 1 hour and then at room temperature overnight. Thereaction mixture was then directly poured over a short columnchromatography (SiO₂, 100 g), eluting successively with 500 mL of EtOAc,THF, EtOAc/EtOH (50/50), EtOH and finally MeOH to yield the titlecompound (1.58 g). MS (m/e): 204.9 (M⁺).

(b) 5-Methanesulfonyl-2-piperazin-1-yl-pyrimidine

The title compound was prepared in analogy to Example 2.25 using3-Dimethylamino-2-methanesulfonyl-allylidene-dimethyl-ammonium; chlorideas starting material. MS (m/e): 243.1 (M+H⁺, 100%).

EXAMPLE 7.4 Preparation of 1-(5-Methanesulfonyl-pyridin-2-yl)-piperazinetrifluoro-acetic acid

The title compound was prepared in analogy to Example 7.1 (b-c) from2-bromo-5-(methanesulfonyl) pyridine and piperazine-1-carboxylic acidtert-butyl ester. MS (m/e): 242.1 (M+H⁺, 100%)

In analogy to Example 5, compounds 633 to 644 of the following tablewere prepared from the acid derivatives and piperazine derivatives:

MW Expl. found No. Systematic Name Starting materials (MH⁺) 633rac-[5-Methanesulfonyl-2- 3-Piperazin-1-yl-5- 527.0(2,2,2-trifluoro-1-methyl- trifluoromethyl- ethoxy)-phenyl]-[4-(5-pyridazine (compound trifluoromethyl-pyridazin- 7.1) and rac-5-3-yl)-piperazin-1-yl]- Methanesulfonyl-2- methanone (2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (compound 3.1) 634 [5-Methanesulfonyl-2-2-Piperazin-1-yl-5- 541.0 (2,2,2-trifluoro-1,1- trifluoromethyl-dimethyl-ethoxy)-phenyl]- pyrimidine (compound [4-(5-trifluoromethyl-2.25) and 5- pyrimidin-2-yl)-piperazin- Methanesulfonyl- 1-yl]-methanone2-(2,2,2-trifluoro-1,1- dimethyl-ethoxy)-benzoic acid (compound 7.2) 635[5-Methanesulfonyl-2- 2-Piperazin-1-yl-5- 527.2 ((S)-2,2,2-trifluoro-1-trifluoromethyl- methyl-ethoxy)-phenyl]- pyrimidine (compound[4-(5-trifluoromethyl- 2.25) and 5- pyrimidin-2-yl)-piperazin-Methanesulfonyl- 1-yl]-methanone 2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (compound 5.6) 636 [5-Methanesulfonyl-2-2-Piperazin-1-yl-5- 527.2 ((R)-2,2,2-trifluoro-1- trifluoromethyl-methyl-ethoxy)-phenyl]- pyrimidine (compound [4-(5-trifluoromethyl-2.25) and 5- pyrimidin-2-yl)-piperazin- Methanesulfonyl- 1-yl]-methanone2-((R)-2,2,2-trifluoro-1- methyl-ethoxy)-benzoic acid (compound 5.7) 637[4-(3-Fluoro-5- 1-(3-Fluoro-5- 558.2 trifluoromethyl-pyridin-2-trifluoromethyl-pyridin- yl)-piperazin-1-yl]-[5- 2-yl)-piperazinemethanesulfonyl-2-(2,2,2- (compound 5.5) and 5- trifluoro-1,1-dimethyl-Methanesulfonyl-2- ethoxy)-phenyl]- (2,2,2-trifluoro-1,1- methanonedimethyl-ethoxy)-benzoic acid (compound 7.2) 638 [5-Methanesulfonyl-2-2-Piperazin-1-yl-5- 513.3 (2,2,2-trifluoro-ethoxy)- trifluoromethyl-phenyl]-[4-(5- pyrimidine (compound trifluoromethyl- 2.25) and 5-pyrimidin-2-yl)-piperazin- Methanesulfonyl- 1-yl]-methanone2-(2,2,2-trifluoro- ethoxy)-benzoic acid (compound 1.5) 639(2-Cyclopropylmethoxy-5- 2-Piperazin-1-yl-5- 485.4methanesulfonyl-phenyl)- trifluoromethyl- [4-(5-trifluoromethyl-pyrimidine (compound pyrimidin-2-yl)-piperazin- 2.25) and 2-1-yl]-methanone Cyclopropylmethoxy-5- methanesulfonyl-benzoic acid(compound 1.4) 640 [4-(2,5-Difluoro-4- 1-(2,5-Difluoro-4- 585.3methanesulfonyl-phenyl)- methanesulfonyl-phenyl)- piperazin-1-yl]-[5-piperazine trifluoro- methanesulfonyl-2-(2,2,2- acetic acidtrifluoro-1,1-dimethyl- (compound 2.20) and ethoxy)-phenyl]-5-Methanesulfonyl- methanone 2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-benzoic acid (compound 7.2) 641 [4-(2,3-Difluoro-4-1-(2,3-Difluoro-4- 585.3 methanesulfonyl-phenyl)-methanesulfonyl-phenyl)- piperazin-1-yl]-[5- piperazine (compoundmethanesulfonyl-2-(2,2,2- 5.3) and 5- trifluoro-1,1-dimethyl-Methanesulfonyl- ethoxy)-phenyl]- 2-(2,2,2-trifluoro-1,1- methanonedimethyl-ethoxy)-benzoic acid (compound 7.2) 642 [4-(2,6-Difluoro-4-1-(2,6-Difluoro-4- 585.2 methanesulfonyl-phenyl)-methanesulfonyl-phenyl)- piperazin-1-yl]-[5- piperazine trifluoro-methanesulfonyl-2-(2,2,2- acetic acid trifluoro-1,1-dimethyl- (compound2.23) and ethoxy)-phenyl]- 5-Methanesulfonyl- methanone2-(2,2,2-trifluoro-1,1- dimethyl-ethoxy)- benzoic acid (compound 7.2)643 rac-[4-(5-Methane 5-Methanesulfonyl-2- 537.3sulfonyl-pyrimidin-2-yl)- piperazin-1-yl-pyrimidine piperazin-1-yl]-[5-(compound 7.3) and methanesulfonyl-2-(2,2,2- rac-5-Methanesulfonyl-2-trifluoro-1-methyl- (2,2,2-trifluoro-1-methyl- ethoxy)-phenyl]-ethoxy)-benzoic acid methanone (compound 3.1) 644 rac-[4-(5-1-(5-Methanesulfonyl- 536.3 Methanesulfonyl-pyridin-pyridin-2-yl)-piperazine 2-yl)-piperazin-1-yl]-[5- trifluoro-acetic acidmethanesulfonyl-2-(2,2,2- (compound 7.4) and trifluoro-1-methyl-rac-5-Methanesulfonyl- ethoxy)-phenyl]- 2-(2,2,2-trifluoro-1- methanonemethyl-ethoxy)-benzoic acid (compound 3.1)

EXAMPLE 645 Preparation of(2-Allyloxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone

The title compound was prepared in analogy to example 62 from(2-Hydroxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone(compound 2.1) and cyclopropyl bromide. MS (m/e): 436.5 (MH⁺, 100%)

EXAMPLE 7.5 Preparation of 2-Benzyloxy-5-methanesulfonyl-benzoic acid

The title compound was prepared in analogy to example 2.10 from methyl5-(methanesulfonyl)salicylate and benzylalcohol. MS (m/e): 305.3 (M−H,100%)

EXAMPLE 646 Preparation of(2-Benzyloxy-5-methanesulfonyl-phenyl)-[4-(3-fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone

The title compound was prepared in analogy to example 5 from1-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazine (compound 5.5)and 2-Benzyloxy-5-methanesulfonyl-benzoic acid (compound 7.5). MS (m/e):538.4 (MH⁺, 100%)

EXAMPLE 647 Preparation of(2-Benzyloxy-5-methanesulfonyl-phenyl)-[4-(2-fluoro-4-methanesulfonyl-phenyl)-piperazin-1-yl]-methanone

The title compound was prepared in analogy to example 5 from1-(2-Fluoro-4-methanesulfonyl-phenyl)-piperazine (commercial) and2-Benzyloxy-5-methanesulfonyl-benzoic acid (compound 7.5). MS (m/e):547.4 (MH⁺, 100%)

EXAMPLE 648 Preparation of[4-(2-Fluoro-4-methanesulfonyl-phenyl)-piperazin-1-yl]-(2-hydroxy-5-methanesulfonyl-phenyl)-methanone

A mixture of 0.915 mmol(2-benzyloxy-5-methanesulfonyl-phenyl)-[4-(2-fluoro-4-methanesulfonyl-phenyl)-piperazin-1-yl]-methanone,0.05 mmol palladium on charcoal (10%) in 12.5 ml methanol washydrogenated at atmospheric pressure at room temperature for 2 hours.After addition of chloroform, the mixture was filtered, and the solventwas evaporated to provide the title compound. MS (m/e): 474.3 (M+NH4⁺,100%)

EXAMPLE 7.6 Preparation of 5-Piperazin-1-yl-2-trifluoromethyl-pyrimidine

(a) 5-Chloro-2-trifluoromethyl-pyrimidine

To a solution of 38 mmol trifluoroacetamidine in 70 ml acetonitrile wasadded 37.92 mmol((Z)-2-Chloro-3-dimethylamino-allylidene)-dimethyl-ammonium hexafluorophosphate (CAS: 291756-76-8) followed by 45.5 mmol triethylamine. Theyellow solution was stirred at room temperature for 5 hours, then pouredonto water and extracted 3 times with ether. The combined extracts weredried over sodium sulfate, filtered and distilled at 760 mm Hg toprovide the title compound. MS (m/e): 182.2 (M⁺, 100%)

(b) 4-(2-Trifluoromethyl-pyrimidin-5-yl)-piperazine-1-carboxylic acidtert-butyl ester

0.26 mmol 5-Chloro-2-trifluoromethyl-pyrimidine was added to 0.26 mmolpiperazine-1-carboxylic acid tert-butyl ester in 1.5 mldimethylacetamide, and the reaction mixture was stirred at 150° C. for10 min. in a microwave oven. After such time, the reaction mixture wasconcentrated and the residue was then purified by column chromatography(SiO₂, Heptane/EtOAc) to yield the title compound. MS (m/e): 333.2(M+H⁺, 100%)

(c) 5-Piperazin-1-yl-2-trifluoromethyl-pyrimidine

The title compound was prepared in analogy to Example 7.1 (c) from4-(2-trifluoromethyl-pyrimidin-5-yl)-piperazine-1-carboxylic acidtert-butyl ester MS (m/e): 233.0 (M+H⁺, 100%)

EXAMPLE 7.7 Preparation of5′-Trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl

(a) 2-Bromo-5-trifluoromethyl-pyrazine

To a suspension of 0.423 mmol copper (II) bromide in THF (1 ml) wasadded dropwise 0.51 mmol tert-butylnitrite at 0° C. within 2 minutes.0.37 mmol 5-Trifluoromethyl-pyrazin-2-ylamine (CAS: 69816-38-2;WO9518097) in solution in THF (0.5 ml) was added dropwise within 5minutes at 0° C. The mixture was stirred at 0° C. for 1 hour, at roomtemperature for 21 hours and quenched with water. The aqueous phase wasextracted with ether. The combined extracts were dried over sodiumsulfate and filtered and concentrated at atmospheric pressure. Theresidue was then purified by column chromatography (SiO₂, ether) toyield the title compound.

(b) 5′-Trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl

The title compound was prepared in analogy to Example 7.6 (b-c) from2-Bromo-5-trifluoromethyl-pyrazine MS (m/e): 233.0 (M+H⁺, 100%)

EXAMPLE 7.8 Preparation of 3-Piperazin-1-yl-6-trifluoromethyl-pyridazine

The title compound was prepared in analogy to Example 7.6 (b-c) from3-Chloro-6-trifluoromethyl-pyridazine (CAS: 258506-68-2). MS (m/e):233.0 (M+H⁺, 100%)

In analogy to Example 5, compounds 649 to 660 of the following tablewere prepared from the acid derivatives and piperazine derivatives:

MW Expl. found No. Systematic Name Starting materials (MH⁺) 649[5-Methanesulfonyl-2- 5-Piperazin-1-yl-2- 527.2 ((S)-2,2,2-trifluoro-1-trifluoromethyl-pyrimidine methyl-ethoxy)- (compound 7.6) and 5-phenyl]-[4-(2- Methanesulfonyl-2-((S)-2,2,2- trifluoromethyl-trifluoro-1-methyl-ethoxy)- pyrimidin-5-yl)- benzoic acid (compound 5.6)piperazin-1-yl]- methanone 650 [5-Methanesulfonyl-2- 5-Piperazin-1-yl-2-527.0 ((R)-2,2,2-trifluoro-1- trifluoromethyl-pyrimidine methyl-ethoxy)-(compound 7.6) and 5- phenyl]-[4- Methanesulfonyl-2-((R)-2,2,2-(2-trifluoromethyl- trifluoro-1-methyl-ethoxy)- pyrimidin-5-yl)- benzoicacid (compound 5.7) piperazin-1-yl]- methanone 651 (2-Isopropoxy-5-5-Piperazin-1-yl-2- 473.0 methanesulfonyl- trifluoromethyl-pyrimidinephenyl)-[4-(2- (compound 7.6) and 2- trifluoromethyl-Isopropoxy-5-methane pyrimidin-5-yl)- sulfonyl-benzoic acidpiperazin-1-yl]- (compound 1.2) methanone 652 [5-Methanesulfonyl-2-5′-Trifluoromethyl-3,4,5,6- 527.2 ((S)-2,2,2-trifluoro-1- tetrahydro-2H-methyl-ethoxy)- [1,2′]bipyrazinyl (compound phenyl]-(5′- 7.7) and5-Methanesulfonyl-2- trifluoromethyl- ((S)-2,2,2-trifluoro-1-methyl-2,3,5,6-tetrahydro- ethoxy)-benzoic acid [1,2′]bipyrazinyl-4-yl)-(compound 5.6) methanone 653 [5-Methanesulfonyl-2-5′-Trifluoromethyl-3,4,5,6- 527.2 ((R)-2,2,2-trifluoro-1- tetrahydro-2H-methyl-ethoxy)- [1,2′]bipyrazinyl (compound phenyl]-(5′- 7.7) and5-Methanesulfonyl- trifluoromethyl- 2-((R)-2,2,2-trifluoro-1-2,3,5,6-tetrahydro- methyl-ethoxy)-benzoic acid [1,2′]bipyrazinyl-4-yl)-(compound 5.7) methanone 654 (2-Isopropoxy-5-5′-Trifluoromethyl-3,4,5,6- 473.4 methanesulfonyl- tetrahydro-2H-phenyl)-(5′- [1,2′]bipyrazinyl (compound trifluoromethyl- 7.7) and2-Isopropoxy-5- 2,3,5,6-tetrahydro- methanesulfonyl-benzoic acid[1,2′]bipyrazinyl-4-yl)- (compound 1.2) methanone 655[5-Methanesulfonyl-2- 3-Piperazin-1-yl-6- 527.3 ((S)-2,2,2-trifluoro-1-trifluoromethyl-pyridazine methyl-ethoxy)- (compound 7.8) and 5-phenyl]-[4-(6- Methanesulfonyl-2-((S)-2,2,2- trifluoromethyl-trifluoro-1-methyl-ethoxy)- pyridazin-3-yl)- benzoic acid (compound 5.6)piperazin-1-yl]- methanone 656 (2-Isopropoxy-5- 3-Piperazin-1-yl-6-473.3 methanesulfonyl- trifluoromethyl-pyridazine phenyl)-[4-(6-(compound 7.8) and 2- trifluoromethyl- Isopropoxy-5-methanepyridazin-3-yl)- sulfonyl-benzoic acid piperazin-1-yl]- (compound 1.2)methanone 657 [5-Methanesulfonyl-2- 3-Piperazin-1-yl-6- 527.3((R)-2,2,2-trifluoro-1- trifluoromethyl-pyridazine methyl-ethoxy)-(compound 7.8) and 5- phenyl]-[4-(6- Methanesulfonyl-2-((R)-2,2,2-trifluoromethyl- trifluoro-1-methyl-ethoxy)- pyridazin-3-yl)- benzoicacid (compound 5.7) piperazin-1-yl]- methanone 658 [5-Methanesulfonyl-2-5-Piperazin-1-yl-2- 541.3 (2,2,2-trifluoro-1,1-trifluoromethyl-pyrimidine dimethyl-ethoxy)- (compound 7.6) and 5-phenyl]-[4-(2- Methanesulfonyl-2-(2,2,2- trifluoromethyl-trifluoro-1,1-dimethyl- pyrimidin-5-yl)- ethoxy)-benzoic acidpiperazin-1-yl]- (compound 7.2) methanone 659 [5-Methanesulfonyl-2-3-Piperazin-1-yl-6- 541.3 (2,2,2-trifluoro-1,1-trifluoromethyl-pyridazine dimethyl-ethoxy)- (compound 7.8) and 5-phenyl]-[4-(6- Methanesulfonyl-2-(2,2,2- trifluoromethyl-trifluoro-1,1-dimethyl- pyridazin-3-yl)- ethoxy)-benzoic acidpiperazin-1-yl]- (compound 7.2) methanone 660 [5-Methanesulfonyl-2-5′-Trifluoromethyl-3,4,5,6- 541.3 (2,2,2-trifluoro-1,1- tetrahydro-2H-dimethyl-ethoxy)- [1,2′]bipyrazinyl (compound phenyl]-(5′- 7.7) and5-Methanesulfonyl-2- trifluoromethyl- (2,2,2-trifluoro-1,1-dimethyl-2,3,5,6-tetrahydro- ethoxy)-benzoic acid [1,2′]bipyrazinyl-4-yl)-(compound 7.2) methanone

The compounds of formula I and their pharmaceutically usable additionsalts possess valuable pharmacological properties. Specifically, it hasbeen found that the compounds of the present invention are goodinhibitors of the glycine transporter I (GlyT-1).

The compounds were investigated in accordance with the test givenhereinafter.

Solutions and Materials

DMEM Complete Medium: Nutrient mixture F-12 (Gibco Life-technologies),fetal bovine serum (FBS) 5%, (Gibco life technologies),Penicillin/Streptomycin 1% (Gibco life technologies), Hygromycin 0.6mg/ml (Gibco life technologies), Glutamine 1 mM Gibco life technologies)Uptake Buffer (UB): 150 mM NaCl, 10 mM Hepes-Tris, pH 7.4, 1 mM CaCl₂,2.5 mM KCl, 2.5 mM MgSO₄, 10 mM (+) D-glucose.

Flp-in™-CHO (Invitrogen Cat n° R758-07)cells stably transfected withmGlyT1b cDNA.

Glycine Uptake Inhibition Assay (mGlyT-1b)

On day 1 mammalian cells, (Flp-in™-CHO), transfected with mGlyT-1b cDNA,were plated at the density of 40,000 cells/well in complete F-12 medium,without hygromycin in 96-culture plates. On day 2, the medium wasaspirated, and the cells were washed twice with uptake buffer (UB). Thecells were then incubated for 20 min at 22° C. with either (i) nopotential competitor, (ii) 10 mM non-radioactive glycine, (iii) aconcentration of a potential inhibitor. A range of concentrations of thepotential inhibitor was used to generate data for calculating theconcentration of inhibitor resulting in 50% of the effect (e.g. IC₅₀,the concentration of the competitor inhibiting glycine uptake of 50%). Asolution was then immediately added containing [³H]-glycine 60 nM (11-16Ci/mmol) and 25 μM non-radioactive glycine. The plates were incubatedwith gentle shaking, and the reaction was stopped by aspiration of themixture and washing (three times) with ice-cold UB. The cells were lysedwith scintillation liquid, shaken 3 hours and the radioactivity in thecells counted using a scintillation counter.

The prepared compounds show an IC₅₀ (μM) at GlyT-1 in the range of0.006-5.0.

The preferred compounds show an IC₅₀ (μM) at GlyT-1 in the range of0.006-0.05, as shown in the table below.

Example No. IC₅₀ (μM) 1 0.039 5 0.012 15 0.015 28 0.012 54 0.05 62 0.01763 0.028 64 0.025 66 0.032 68 0.008 70 0.008 71 0.008 72 0.026 74 0.01678 0.012 80 0.029 84 0.04 88 0.007 92 0.05 95 0.035 100 0.02 104 0.046105 0.039 109 0.021 111 0.035 112 0.024 116 0.019 117 0.044 118 0.024128 0.02 131 0.03 132 0.038 135 0.041 136 0.027 137 0.027 138 0.017 1390.024 142 0.034 144 0.045 145 0.015 146 0.019 147 0.031 148 0.036 1640.019 165 0.47 167 0.016 169 0.012 170 0.031 172 0.019 180 0.036 1820.03 184 0.022 186 0.048 194 0.047 196 0.041 202 0.024 207 0.023 2090.041 210 0.039 211 0.043 212 0.029 213 0.021 215 0.049 228 0.047 2340.043 244 0.042 247 0.03 249 0.032 250 0.061 251 0.032 256 0.032 2580.086 260 0.043 261 0.043 262 0.042 281 0.021 282 0.027 283 0.008 2840.01 285 0.042 287 0.033 288 0.025 289 0.018 290 0.017 291 0.013 2920.021 293 0.034 294 0.037 295 0.016 296 0.043 298 0.021 299 0.044 3000.016 301 0.03 302 0.013 303 0.006 311 0.045 313 0.018 317 0.041 3190.031 321 0.018 322 0.028 324 0.039 325 0.033 328 0.032 329 0.016 3300.018 363 0.008 367 0.036 369 0.032 371 0.041 372 0.006 373 0.035 3750.035 393 0.032 400 0.023 407 0.027 408 0.037 411 0.045 412 0.033 4130.03 417 0.046 430 0.037 435 0.029 437 0.026 438 0.047 439 0.021 4590.04 461 0.046 464 0.02 465 0.04 466 0.026 468 0.02 469 0.02 470 0.03475 0.04 481 0.03 488 0.039 491 0.037 494 0.03 504 0.025 505 0.024 5060.046 507 0.031 408 0.026 509 0.03 510 0.015 514 0.045 515 0.04 5170.035 518 0.033 519 0.035 524 0.012 525 0.021 526 0.009 527 0.006 5280.015 529 0.013 530 0.0057 531 0.028 534 0.049 537 0.03 546 0.035 5540.019 557 0.042 558 0.029 561 0.038 562 0.044 563 0.043 564 0.041 5660.03 568 0.044 570 0.046 571 0.05 573 0.037 574 0.034 576 0.039 5780.041 589 0.032 595 0.049 637 0.047

The present invention also provides pharmaceutical compositionscontaining compounds of formula I or pharmaceutically acceptable saltsof the compounds of formula I and a pharmaceutically acceptable carrier.Such pharmaceutical compositions can be in the form of tablets, coatedtablets, dragées, hard and soft gelatine capsules, solutions, emulsionsor suspensions. The pharmaceutical compositions also can be in the formof suppositories or injectable solutions.

The pharmaceutical compositions of the invention, in addition to one ormore compounds of the invention, contain a pharmaceutically acceptablecarrier. Suitable pharmaceutical acceptable carriers includepharmaceutically inert, inorganic or organic carriers. Lactose, cornstarch or derivatives thereof, talc, stearic acids or its salts and thelike can be used, for example, as such carriers for tablets, coatedtablets, dragées and hard gelatine capsules. Suitable carriers for softgelatine capsules are, for example, vegetable oils, waxes, fats,semi-solid and liquid polyols and the like. Depending on the nature ofthe active substance no carriers are however usually required in thecase of soft gelatine capsules. Suitable carriers for the production ofsolutions and syrups are, for example, water, polyols, glycerol,vegetable oil and the like. Suitable carriers for suppositories are, forexample, natural or hardened oils, waxes, fats, semi-liquid or liquidpolyols and the like.

In addition, the pharmaceutical compositions can contain preservatives,solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners,colorants, flavorants, salts for varying the osmotic pressure, buffers,masking agents or antioxidants. They can also contain still othertherapeutically valuable substances.

Thus, pharmaceutical compositions containing a compound of formula I ora pharmaceutically acceptable salt thereof and a therapeutically inertcarrier are also an object of the present invention, as is a process fortheir production, which comprises bringing one or more compounds offormula I and/or pharmaceutically acceptable acid addition salts and, ifdesired, one or more other therapeutically valuable substances into agalenical administration form together with one or more therapeuticallyinert carriers.

The most preferred indications in accordance with the present inventionare those, which include disorders of the central nervous system, forexample the treatment or prevention of schizophrenia, cognitiveimpairment and Alzheimer's disease.

Thus, the invention also provides a method of inhibiting glycine uptakecomprising administering to an individual a glycine inhibiting amount ofone or more compounds of formula I. The invention further provides amethod of inhibiting glycine uptake which comprises administering to anindividual a glycine inhibiting amount of one of the following compounds

-   1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-(3-chlorophenyl)-piperazine,-   1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-(4-fluorophenyl)-piperazine,-   1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-[3-(trifluoromethyl)phenyl]-piperazine,-   4-(3-amino-4-nitrophenyl)-1-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-2-methyl-piperazine,-   1-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-2-methyl-4-(4-nitrophenyl)-piperazine,-   4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-2-methyl-1-(4-nitrophenyl)-piperazine,-   1-(2-chloro-4-nitrophenyl)-4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-piperazine,-   1-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-4-(2,4-dinitrophenyl)-2-methyl-piperazine,-   1-(4-chloro-2-nitrophenyl)-4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-piperazine    or-   4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-1-(2,4-dinitrophenyl)-2-methyl-piperazine.

The invention provides a method of treating an illness selected from thegroup consisting of psychoses, pain, disfunction in memory and learning,schizophrenia, dementia, attention deficit disorders, and Alzheimer'sdisease, which method comprises administering to an individual aneffective amount of one or more compounds of formula I. The inventionfurther provides a method of treating an illness selected from the groupconsisting of psychoses, pain, disfunction in memory and learning,schizophrenia, dementia, attention deficit disorders, and Alzheimer'sdisease, which method comprises administering to an individual aneffective amount of one or more compounds of the following compounds1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-(3-chlorophenyl)-piperazine,

-   1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-(4-fluorophenyl)-piperazine,-   1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-[3-(trifluoromethyl)phenyl]-piperazine,-   4-(3-amino-4-nitrophenyl)-1-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-2-methyl-piperazine,-   1-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-2-methyl-4-(4-nitrophenyl)-piperazine,-   4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-2-methyl-1-(4-nitrophenyl)-piperazine,-   1-(2-chloro-4-nitrophenyl)-4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-piperazine,-   1-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-4-(2,4-dinitrophenyl)-2-methyl-piperazine,-   1-(4-chloro-2-nitrophenyl)-4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-piperazine    or-   4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-1-(2,4-dinitrophenyl)-2-methyl-piperazine.

In particular, the method provides a method of treating schizophrenia,which method comprises administering to an individual an effectiveamount of one or more compounds of formula I. The invention furtherprovides a method of treating schizophrenia, which method comprisesadministering to an individual an effective amount of one or morecompounds of the following compounds

-   1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-(3-chlorophenyl)-piperazine,-   1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-(4-fluorophenyl)-piperazine,-   1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-[3-(trifluoromethyl)phenyl]-piperazine,-   4-(3-amino-4-nitrophenyl)-1-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-2-methyl-piperazine,-   1-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-2-methyl-4-(4-nitrophenyl)-piperazine,-   4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-2-methyl-1-(4-nitrophenyl)-piperazine,-   1-(2-chloro-4-nitrophenyl)-4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-piperazine,-   1-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-4-(2,4-dinitrophenyl)-2-methyl-piperazine,-   1-(4-chloro-2-nitrophenyl)-4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-piperazine    or-   4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-1-(2,4-dinitrophenyl)-2-methyl-piperazine.

In particular, the method provides a method of treating Alzheimer'sdisease, which method comprises administering to an individual aneffective amount of one or more compounds of formula I. The inventionfurther provides a method of treating Alzhemier's disease, which methodcomprises administering to an individual an effective amount of one ormore compounds of the following compounds

-   1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-(3-chlorophenyl)-piperazine,-   1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-(4-fluorophenyl)-piperazine,-   1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-[3-(trifluoromethyl)phenyl]-piperazine,-   4-(3-amino-4-nitrophenyl)-1-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-2-methyl-piperazine,-   1-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-2-methyl-4-(4-nitrophenyl)-piperazine,-   4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-2-methyl-1-(4-nitrophenyl)-piperazine,-   1-(2-chloro-4-nitrophenyl)-4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-piperazine,-   1-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-4-(2,4-dinitrophenyl)-2-methyl-piperazine,-   1-(4-chloro-2-nitrophenyl)-4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-piperazine    or-   4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-1-(2,4-dinitrophenyl)-2-methyl-piperazine.

The compounds and compositions of the present invention can beadministered in a conventional manner, for example, orally, rectally, orparenterally. The pharmaceutical compositions of the invention can beadministered orally, for example, in the form of tablets, coatedtablets, dragées, hard and soft gelatine capsules, solutions, emulsionsor suspensions. The pharmaceutical compositions also can be administeredrectally, for example, in the form of suppositories or parenterally, forexample, in the form of injectable solutions.

The dosage at which a compound of the invention can be administered canvary within wide limits and will, of course, have to be adjusted to theindividual requirements in each particular case. In the case of oraladministration the dosage for adults can vary from about 0.01 mg toabout 1000 mg per day of a compound of general formula I or of thecorresponding amount of a pharmaceutically acceptable salt thereof. Thedaily dosage may be administered as single dose or in divided doses and,in addition, the upper limit can also be exceeded when this is found tobe indicated.

Tablet Formulation (Wet Granulation) mg/tablet Item Ingredients 5 mg 25mg 100 mg 500 mg 1. Compound of formula I 5 25 100 500 2. LactoseAnhydrous DTG 125 105 30 150 3. Sta-Rx 1500 6 6 6 30 4. MicrocrystallineCellulose 30 30 30 150 5. Magnesium Stearate 1 1 1 1 Total 167 167 167831Manufacturing Procedure

-   1. Mix items 1, 2, 3 and 4 and granulate with purified water.-   2. Dry the granules at 50° C.-   3. Pass the granules through suitable milling equipment.-   4. Add item 5 and mix for three minutes; compress on a suitable    press.

Capsule Formulation mg/capsule Item Ingredients 5 mg 25 mg 100 mg 500mg 1. Compound of formula I 5 25 100 500 2. Hydrous Lactose 159 123 148— 3. Corn Starch 25 35 40 70 4. Talc 10 15 10 25 5. Magnesium Stearate 12 2 5 Total 200 200 300 600Manufacturing Procedure

-   1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes.-   2. Add items 4 and 5 and mix for 3 minutes.-   3. Fill into a suitable capsule.

1. A compound of formula

wherein Ar is unsubstituted or substituted aryl or 6-membered heteroarylcontaining one, two or three nitrogen atoms, wherein the substitutedaryl and the substituted heteroaryl groups are substituted by one ormore substituents selected from the group consisting of hydroxy,halogen, NO₂, CN, (C₁-C₆)-alkyl, (C₁-C₆)-alkyl substituted by halogen,(C₁-C₆)-alkyl substituted by hydroxy, (CH₂)_(n)—(C₁-C₆)-alkoxy,(C₁-C₆)-alkoxy substituted by halogen, NR⁷R⁸, C(O)R⁹, SO₂R¹⁰, and—C(CH₃)═NOR⁷, or are substituted by a 5-membered aromatic heterocyclecontaining 1-4 heteroatoms selected from N and O, which is optionallysubstituted by (C₁-C₆)-alkyl; R¹ is hydrogen or (C₁-C₆)-alkyl; R² ishydrogen, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₁-C₆)-alkyl substituted byhalogen, (C₁-C₆)-alkyl substituted by hydroxy,(CH₂)_(n)—(C₃-C₇)-cycloalkyl optionally substituted by (C₁-C₆)-alkoxy orby halogen, CH(CH₃)—(C₃-C₇)-cycloalkyl, (CH₂)_(n+1)—C(O)—R⁹,(CH₂)_(n+1)—CN, bicyclo[2.2.1]heptyl, (CH₂)_(n+1)—O—(C₁-C₆)-alkyl,(CH₂)_(n)-heterocycloalkyl, (CH₂)_(n)-aryl or (CH₂)_(n)-5 or 6-memberedheteroaryl containing one, two or three heteroatoms selected from thegroup consisting of oxygen, sulphur or nitrogen wherein aryl,heterocycloalkyl and heteroaryl are unsubstituted or substituted by oneor more substituents selected from the group consisting of hydroxy,halogen, (C₁-C₆)-alkyl and (C₁-C₆)-alkoxy; R³, R⁴ and R⁶ are eachindependently hydrogen, hydroxy, halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxyor O—(C₃-C₆)-cycloalkyl; R⁵ is NO₂, CN, C(O)R⁹ or SO₂R¹⁰; R⁷ and R⁸ areeach independently hydrogen or (C₁-C₆)-alkyl; R⁹ is hydrogen,(C₁-C₆)-alkyl, (C₁-C₆)-alkoxy or NR⁷R⁸; R¹⁰ is (C₁-C₆)-alkyl optionallysubstituted by halogen, (CH₂)_(n)—(C₃-C₆)-cycloalkyl,(CH₂)_(n)—(C₃-C₆)-alkoxy, (CH₂)_(n)-heterocycloalkyl or NR⁷R⁸; n is 0,1, or 2; or a pharmaceutically acceptable acid addition salt thereof. 2.A compound of formula

wherein Ar is substituted aryl or unsubstituted or substituted6-membered heteroaryl containing one, two or three nitrogen atoms, andwherein the substituted aryl and the substituted heteroaryl groups aresubstituted by one or more substituents selected from the groupconsisting of hydroxy, halogen, NO₂, CN, (C₁-C₆)-alkyl, (C₁-C₆)-alkylsubstituted by halogen, (C₁-C₆)-alkoxy, (C₁-C₆)-alkoxy substituted byhalogen, NR⁷R⁸, C(O)R⁹ and SO₂R¹⁰; R¹ is hydrogen or (C₁-C₆)-alkyl; R²is (C₁-C₆)-alkyl, (C₁-C₆)-alkyl substituted by halogen,(C₃-C₆)-cycloalkyl, heterocycloalkyl, (C₁-C₆)-alkyl-(C₃-C₆)-cycloalkyl,(C₁-C₆)-alkyl-heterocycloalkyl, (C₁-C₆)-alkyl-C(O)—R⁹, (C₁-C₆)-alkyl-CN,(C₂-C₆)-alkyl-O—R¹³, (C₂-C₆)-alkyl-NR⁷R⁸, aryl, 6-membered heteroarylcontaining one, two or three nitrogen atoms, (C₁-C₆)-alkyl-aryl or(C₁-C₆)-alkyl-5 or -6-membered heteroaryl containing one, two or threeheteroatoms selected from the group consisting of oxygen, sulphur ornitrogen wherein aryl, heterocycloalkyl and heteroaryl are unsubstitutedor substituted by one or more substituents selected from the groupconsisting of hydroxy, halogen, (C₁-C₆)-alkyl and (C₁-C₆)-alkoxy; R³, R⁴and R⁶ are each independently hydrogen, hydroxy, halogen, CN,(C₁-C₆)-alkyl, (C₁-C₆)-alkoxy or NR⁷R⁸; R⁵ is NO₂, CN, C(O)R⁹, SO₂R¹⁰ orNR¹¹R¹²; R⁷ and R⁸ are each independently hydrogen or (C₁-C₆)-alkyl; R⁹is hydroxy, (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl, (C₁-C₆)-alkoxy or NR⁷R⁸;R¹⁰ is (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl or NR⁷R⁸; R¹¹ and R¹² are eachindependently hydrogen, C(O)—(C₁-C₆)-alkyl, or SO₂—(C₁-C₆)-alkyl, orform together with the N-atom to which they are attached a 5-memberedheteroaryl group, optionally substituted by halogen, (C₁-C₆)-alkyl,(C₁-C₆)-alkyl substituted by halogen or (C₃-C₆)-cycloalkyl; R¹³ ishydroxy, (C₁-C₆)-alkyl or (C₃-C₆)-cycloalkyl; or a pharmaceuticallyacceptable acid addition salt thereof.
 3. A compound of formula Iaccording to claim 1, wherein Ar is a substituted 6-membered heteroarylgroup containing one, two or three nitrogen atoms, R² is (C₁-C₆)-alkylor CH₂)_(n)—(C₃-C₇)-cycloalkyl, and R⁵ is SO₂CH₃.
 4. A compound offormula I according to claim 3, wherein the compound is selected fromthe group consisting of[4-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-(2-cyclopropylmethoxy-5-methanesulfonyl-phenyl)-methanone,6-[4-(2-cyclopentyloxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-nicotinonitrile,(2-cyclopentyloxy-5-methanesulfonyl-phenyl)-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone,[4-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-(2-cyclopentyloxy-5-methanesulfonyl-phenyl)-methanone,(2-cyclopentyloxy-5-methanesulfonyl-phenyl)-[4-(6-trifluoromethyl-pyridin-3-yl)-piperazin-1-yl]-methanone,[4-(3-fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanoneand(2-cyclopentyloxy-5-methanesulfonyl-phenyl)-[4-(3-fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone.5. A compound of formula I according to claim 1, wherein Ar is asubstituted 6-membered heteroaryl group containing one, two or threenitrogen atoms, R² is (C₁-C₆)-alkyl substituted by halogen and R⁵ isSO₂CH₃.
 6. A compound of formula I according to claim 5, wherein thecompound is selected from the group consisting ofrac-[4-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone,rac-[5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone,rac-[4-(5-bromo-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone,rac-[4-(3-fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone,rac-[5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-[4-(6-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone,[5-methanesulfonyl-2-((S orR)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone,[5-methanesulfonyl-2-((R orS)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone,[4-(3-fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanoneand[4-(3-fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-phenyl]-methanone.7. A process for preparing a compound of formula

wherein Ar is unsubstituted or substituted aryl or 6-membered heteroarylcontaining one, two or three nitrogen atoms, wherein the substitutedaryl and the substituted heteroaryl groups are substituted by one ormore substituents selected from the group consisting of hydroxy,halogen, NO₂, CN, (C₁-C₆)-alkyl, (C₁-C₆)-alkyl substituted by halogen,(C₁-C₆)-alkyl substituted by hydroxy, (CH₂)_(n)—(C₁-C₆)-alkoxy,(C₁-C₆)-alkoxy substituted by halogen, NR⁷R⁸, C(O)R⁹, SO₂R¹⁰, and—C(CH₃)═NOR⁷, or are substituted by a 5-membered aromatic heterocyclecontaining 1-4 heteroatoms selected from N and O, which is optionallysubstituted by (C₁-C₆)-alkyl; R¹ is hydrogen or (C₁-C₆)-alkyl; R² ishydrogen, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₁-C₆)-alkyl substituted byhalogen, (C₁-C₆)-alkyl substituted by hydroxy,(CH₂)_(n)—(C₃-C₇)-cycloalkyl optionally substituted by (C₁-C₆)-alkoxy orby halogen, CH(CH₃)—(C₃-C₇)-cycloalkyl, (CH₂)_(n+1)—C(O)—R⁹,(CH₂)_(n+1)—CN, bicyclo [2.2.1]heptyl, (CH₂)_(n+1)—O—(C₁-C₆)-alkyl,(CH₂)_(n)-heterocycloalkyl, (CH₂)_(n)-aryl or (CH₂)_(n)-5 or 6-memberedheteroaryl containing one, two or three heteroatoms selected from thegroup consisting of oxygen, sulphur or nitrogen wherein aryl,heterocycloalkyl and heteroaryl are unsubstituted or substituted by oneor more substituents selected from the group consisting of hydroxy,halogen, (C₁-C₆)-alkyl and (C₁-C₆)-alkoxy; R³, R⁴ and R⁶ are eachindependently hydrogen, hydroxy, halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxyor O—(C₃-C₆)-cycloalkyl; R⁵ is NO₂, CN, C(O)R⁹ or SO₂R¹⁰; R⁷ and R⁸ areeach independently hydrogen or (C₁-C₆)-alkyl; R⁹ is hydrogen,(C₁-C₆)-alkyl, (C₁-C₆)-alkoxy or NR⁷R⁸; R¹⁰ is (C₁-C₆)-alkyl optionallysubstituted by halogen, (CH₂)_(n)—(C₃-C₆)-cycloalkyl,(CH₂)_(n)—(C₃-C₆)-alkoxy, (CH₂)_(n)-heterocycloalkyl or NR⁷R⁸; n is 0,1, or 2; or a pharmaceutically acceptable acid addition salt thereof,which process comprises reacting a compound of formula

with a compound of formula

in the presence of an activating agent to produce a compound of formula

wherein the substituents are as defined above.
 8. A process according toclaim 7, wherein the activating agent is TBTU(2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate).
 9. A process for preparing a compound of formula

wherein Ar is unsubstituted or substituted aryl or 6-membered heteroarylcontaining one, two or three nitrogen atoms, wherein the substitutedheteroaryl groups are substituted by one or more substituents selectedfrom the group consisting of hydroxy, halogen, NO₂, CN, (C₁-C₆)-alkyl,(C₁-C₆)-alkyl substituted by halogen, (C₁-C₆)-alkyl substituted byhydroxy, (CH₂)_(n)—(C₁-C₆)-alkoxy, (C₁-C₆)-alkoxy substituted byhalogen, NR⁷R⁸, C(O)R⁹, SO₂R¹⁰, and —C(CH₃)═NOR⁷, or are substituted bya 5-membered aromatic heterocycle containing 1-4 heteroatoms selectedfrom N and O, which is optionally substituted by (C₁-C₆)-alkyl; R¹ ishydrogen or (C₁-C₆)-alkyl; R² is hydrogen, (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, (C₁-C₆)-alkyl substituted by halogen, (C₁-C₆)-alkylsubstituted by hydroxy, (CH₂)_(n)—(C₃-C₇)-cycloalkyl optionallysubstituted by (C₁-C₆)-alkoxy or by halogen, CH(CH₃)—(C₃-C₇)-cycloalkyl,(CH₂)_(n+1)—C(O)—R⁹, (CH₂)_(n+1)—CN, bicyclo [2.2.1]heptyl,(CH₂)_(n+1)—O—(C₁-C₆)-alkyl, (CH₂)_(n)-heterocycloalkyl, (CH₂)_(n)-arylor (CH₂)_(n)-5 or 6-membered heteroaryl containing one, two or threeheteroatoms selected from the group consisting of oxygen, sulphur ornitrogen wherein aryl, heterocycloalkyl and heteroaryl are unsubstitutedor substituted by one or more substituents selected from the groupconsisting of hydroxy, halogen, (C₁-C₆)-alkyl and (C₁-C₆)-alkoxy; R³, R⁴and R⁶ are each independently hydrogen, hydroxy, halogen, (C₁-C₆)-alkyl,(C₁-C₆)-alkoxy or O—(C₃-C₆)-cycloalkyl; R⁵ is NO₂, CN, C(O)R⁹ or SO₂R¹⁰;R⁷ and R⁸ are each independently hydrogen or (C₁-C₆)-alkyl; R⁹ ishydrogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy or NR⁷R⁸; R¹⁰ is (C₁-C₆)-alkyloptionally substituted by halogen, (CH₂)_(n)—(C₃-C₆)-cycloalkyl,(CH₂)_(n)—(C₃-C₆)-alkoxy, (CH₂)_(n)-heterocycloalkyl or NR⁷R⁸; n is 0,1, or 2; or a pharmaceutically acceptable acid addition salt thereof,which process comprises reacting a compound of formula

with a compound of formulaR²OH optionally in the presence of a catalyst and a base to produce acompound of formula

wherein X is halogen and the other substituents are as defined above.10. The process according to claim 9 wherein the catalyst is Cu(I)I andthe base is potassium carbonate, cesium carbonate or sodium.
 11. Aprocess for preparing a compound of formula

wherein Ar is unsubstituted or substituted aryl or 6-membered heteroarylcontaining one, two or three nitrogen atoms, wherein the substitutedheteroaryl groups are substituted by one or more substituents selectedfrom the group consisting of hydroxy, halogen, NO₂, CN, (C₁-C₆)-alkyl,(C₁-C₆)-alkyl substituted by halogen, (C₁-C₆)-alkyl substituted byhydroxy, (CH₂)_(n)—(C₁-C₆)-alkoxy, (C₁-C₆)-alkoxy substituted byhalogen, NR⁷R⁸, C(O)R⁹, SO₂R¹⁰, and —C(CH₃)═NOR⁷, or are substituted bya 5-membered aromatic heterocycle containing 1-4 heteroatoms selectedfrom N and O, which is optionally substituted by (C₁-C₆)-alkyl; R¹ ishydrogen or (C₁-C₆)-alkyl; R² is hydrogen, (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, (C₁-C₆)-alkyl substituted by halogen, (C₁-C₆)-alkylsubstituted by hydroxy, (CH₂)_(n)—(C₃-C₇)-cycloalkyl optionallysubstituted by (C₁-C₆)-alkoxy or by halogen, CH(CH₃)—(C₃-C₇)-cycloalkyl,(CH₂)_(n+1)—C(O)—R⁹, (CH₂)_(n+1)—CN, bicyclo[2.2.1]heptyl,(CH₂)_(n+1)—O—(C₁-C₆)-alkyl, (CH₂)_(n)-heterocycloalkyl, (CH₂)_(n)-arylor (CH₂)_(n)-5 or 6-membered heteroaryl containing one, two or threeheteroatoms selected from the group consisting of oxygen, sulphur ornitrogen wherein aryl, heterocycloalkyl and heteroaryl are unsubstitutedor substituted by one or more substituents selected from the groupconsisting of hydroxy, halogen, (C₁-C₆)-alkyl and (C₁-C₆)-alkoxy; R³, R⁴and R⁶ are each independently hydrogen, hydroxy, halogen, (C₁-C₆)-alkyl,(C₁-C₆)-alkoxy or O—(C₃-C₆)-cycloalkyl; R⁵ is NO₂, CN, C(O)R⁹ or SO₂R¹⁰;R⁷ and R⁸ are each independently hydrogen or (C₁-C₆)-alkyl; R⁹ ishydrogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy or NR⁷R⁸; R¹⁰ is (C₁-C₆)-alkyloptionally substituted by halogen, (CH₂)_(n)—(C₃-C₆)-cycloalkyl,(CH₂)_(n)—(C₃-C₆)-alkoxy, (CH₂)_(n)-heterocycloalkyl or NR⁷R⁸; n is 0,1, or 2; or a pharmaceutically acceptable acid addition salt thereof,which process comprises reacting a compound of formula

with a compound of formulaR²X in the presence of a base and optionally in the presence ofmicrowaves to produce a compound of formula

wherein X is halogen, mesylate or triflate and the other substituentsare as defined above.
 12. A process for preparing a compound of formula

wherein Ar is unsubstituted or substituted aryl or 6-membered heteroarylcontaining one, two or three nitrogen atoms, wherein the substitutedheteroaryl groups are substituted by one or more substituents selectedfrom the group consisting of hydroxy, halogen, NO₂, CN, (C₁-C₆)-alkyl,(C₁-C₆)-alkyl substituted by halogen, (C₁-C₆)-alkyl substituted byhydroxy, (CH₂)_(n)—(C₁-C₆)-alkoxy, (C₁-C₆)-alkoxy substituted byhalogen, NR⁷R⁸, C(O)R⁹, SO₂R¹⁰, and —C(CH₃)═NOR⁷, or are substituted bya 5-membered aromatic heterocycle containing 1-4 heteroatoms selectedfrom N and O, which is optionally substituted by (C₁-C₆)-alkyl; R¹ ishydrogen or (C₁-C₆)-alkyl; R² is hydrogen, (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, (C₁-C₆)-alkyl substituted by halogen, (C₁-C₆)-alkylsubstituted by hydroxy, (CH₂)_(n)—(C₃-C₇)-cycloalkyl optionallysubstituted by (C₁-C₆)-alkoxy or by halogen, CH(CH₃)—(C₃-C₇)-cycloalkyl,(CH₂)_(n+1)—C(O)—R⁹, (CH₂)_(n+1)—CN, bicyclo[2.2.1]heptyl,(CH₂)_(n+1)—O—(C₁-C₆)-alkyl, (CH₂)_(n)-heterocycloalkyl, (CH₂)_(n)-arylor (CH₂)_(n)-5 or 6-membered heteroaryl containing one, two or threeheteroatoms selected from the group consisting of oxygen, sulphur ornitrogen wherein aryl, heterocycloalkyl and heteroaryl are unsubstitutedor substituted by one or more substituents selected from the groupconsisting of hydroxy, halogen, (C₁-C₆)-alkyl and (C₁-C₆)-alkoxy; R³, R⁴and R⁶ are each independently hydrogen, hydroxy, halogen, (C₁-C₆)-alkyl,(C₁-C₆)-alkoxy or O—(C₃-C₆)-cycloalkyl; R⁵ is NO₂, CN, C(O)R⁹ or SO₂R¹⁰;R⁷ and R⁸ are each independently hydrogen or (C₁-C₆)-alkyl; R⁹ ishydrogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy or NR⁷R⁸; R¹⁰ is (C₁-C₆)-alkyloptionally substituted by halogen, (CH₂)_(n)—(C₃-C₆)-cycloalkyl,(CH₂)_(n)—(C₃-C₆)-alkoxy, (CH₂)_(n)-heterocycloalkyl or NR⁷R⁸; n is 0,1, or 2; or a pharmaceutically acceptable acid addition salt thereof,which process comprises reacting a compound of formula

with a compound of formulaR²OH under Mitsunobu conditions in the presence of a phosphine toproduce a compound of formula

wherein the substituents are as defined above.
 13. A process forpreparing a compound of formula

wherein Ar is unsubstituted or substituted aryl or 6-membered heteroarylcontaining one, two or three nitrogen atoms, wherein the substitutedaryl and the substituted heteroaryl groups are substituted by one ormore substituents selected from the group consisting of hydroxy,halogen, NO₂, CN, (C₁-C₆)-alkyl, (C₁-C₆)-alkyl substituted by halogen,(C₁-C₆)-alkyl substituted by hydroxy, (CH₂)_(n)—(C₁-C₆)-alkoxy,(C₁-C₆)-alkoxy substituted by halogen, NR⁷R⁸, C(O)R⁹, SO₂R¹⁰, and—C(CH₃)═NOR⁷, or are substituted by a 5-membered aromatic heterocyclecontaining 1-4 heteroatoms selected from N and O, which is optionallysubstituted by (C₁-C₆)-alkyl; R¹ is hydrogen or (C₁-C₆)-alkyl; R² ishydrogen, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₁-C₆)-alkyl substituted byhalogen, (C₁-C₆)-alkyl substituted by hydroxy,(CH₂)_(n)—(C₃-C₇)-cycloalkyl optionally substituted by (C₁-C₆)-alkoxy orby halogen, CH(CH₃)—(C₃-C₇)-cycloalkyl, (CH₂)_(n+1)—C(O)—R⁹,(CH₂)_(n+1)—CN, bicyclo[2.2.1]heptyl, (CH₂)_(n+1)—O—(C₁-C₆)-alkyl,(CH₂)_(n)-heterocycloalkyl, (CH₂)_(n)-aryl or (CH₂)_(n)-5 or 6-memberedheteroaryl containing one, two or three heteroatoms selected from thegroup consisting of oxygen, sulphur or nitrogen wherein aryl,heterocycloalkyl and heteroaryl are unsubstituted or substituted by oneor more substituents selected from the group consisting of hydroxy,halogen, (C₁-C₆)-alkyl and (C₁-C₆)-alkoxy; R³, R⁴ and R⁶ are eachindependently hydrogen, hydroxy, halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxyor O—(C₃-C₆)-cycloalkyl; R⁵ is NO₂, CN, C(O)R⁹ or SO₂R¹⁰, R⁷ and R⁸ areeach independently hydrogen or (C₁-C₆)-alkyl; R⁹ is hydrogen,(C₁-C₆)-alkyl, (C₁-C₆)-alkoxy or NR⁷R⁸; R¹⁰ is (C₁-C₆)-alkyl optionallysubstituted by halogen, (CH₂)_(n)—(C₃-C₆)-cycloalkyl,(CH₂)_(n)—(C₃-C₆)-alkoxy, (CH₂)_(n)-heterocycloalkyl or NR⁷R⁸; n is 0,1, or 2; or a pharmaceutically acceptable acid addition salt thereof,which process comprises reacting a compound of formula

with a compound of formulaArX to produce a compound of formula

wherein X is halogen and the other substituents are as defined above.14. A composition comprising one or more compounds of formula

wherein Ar is unsubstituted or substituted 6-membered heteroarylcontaining one, two or three nitrogen atoms, wherein the substitutedheteroaryl groups are substituted by one or more substituents selectedfrom the group consisting of hydroxy, halogen, NO₂, CN, (C₁-C₆)-alkyl,(C₁-C₆)-alkyl substituted by halogen, (C₁-C₆)-alkyl substituted byhydroxy, (CH₂)_(n)—(C₁-C₆)-alkoxy, (C₁-C₆)-alkoxy substituted byhalogen, NR⁷R⁸, C(O)R⁹, SO₂R¹⁰, and —C(CH₃)═NOR⁷, or are substituted bya 5-membered aromatic heterocycle containing 1-4 heteroatoms selectedfrom N and O, which is optionally substituted by (C₁-C₆)-alkyl; R¹ ishydrogen or (C₁-C₆)-alkyl; R² is hydrogen, (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, (C₁-C₆)-alkyl substituted by halogen, (C, C₆)-alkylsubstituted by hydroxy, (CH₂)_(n)—(C₃-C₇)-cycloalkyl optionallysubstituted by (C₁-C₆)-alkoxy or by halogen, CH(CH₃—(C₃-C₇)-cycloalkyl,(CH₂)_(n+−)C(O)—R⁹, (CH₂)_(n+1−)—CN, bicyclo(2.2.1]heptyl,(CH₂)_(n+1)—O—(C₁-C₆)-alkyl, (CH₂)_(n)-heterocycloalkyl, (CH₂)_(n)-arylor (CH₂)_(n)-5 or 6-membered heteroaryl containing one, two or threeheteroatorns selected from the group consisting of oxygen, sulphur ornitrogen wherein aryl, heterocycloalkyl and heteroaryl are unsubstitutedor substituted by one or more substituents selected from the groupconsisting of hydroxy, halogen, (C₁-C₆)-alkyl and (C₁-C₆)-alkoxy; R³, R⁴and R⁶ are each independently hydrogen, hydroxy, halogen, (C₁-C₆)-alkyl,(C₁-C₆)-allcoxy or O—(C₃-C₆)-cycloalkyl; R5 is NO₂, CN, C(O)R⁹or S₂R¹⁰;R⁷ and R⁸ are each independently hydrogen or (C₁-C₆)-alkyl; R⁹ ishydrogen, (C₁-C₆)-alkyl, (C₁-C₆)-allcoxy or NR⁷R⁸; R₁₀ is (C₁-C₆)-alkyloptionally substituted by halogen, (CH₂)_(n)—(C₃-C₆)-cycloalkyl(CH₂)_(n)—(C₃-C₆)-alkoxy, (CH₂)_(n)-heterocycloalkyl or NR⁷R⁸; n is 0, 1, or2; or a pharmaceutically acceptable acid addition salt thereof, anda pharmaceutically acceptable excipient.
 15. A method of treatingschizophrenia which comprises administering to an individual aneffective amount of one or more compounds of formula

wherein Ar is unsubstituted or substituted 6-membered heteroarylcontaining one, two or three nitrogen atoms, wherein the substitutedheteroaryl groups are substituted by one or more substituents selectedfrom the group consisting of hydroxy, halogen, NO₂, CN, (C₁-C₆)-alkyl,(C₁-C₆)-alkyl substituted by halogen, (C₁-C₆)-alkyl substituted byhydroxy, (CH₂)_(n)—(C₁-C₆)-alkoxy, (C₁-C₆)-alkoxy substituted byhalogen, NR⁷R⁸, C(O)R⁹, SO₂R¹⁰, and —C(CH₃)═NOR⁷, or are substituted bya 5-membered aromatic heterocycle containing 1-4 heteroatorns selectedfrom N and O, which is optionally substituted by (C₁-C₆)-alkyl; R¹ ishydrogen or (C₁-C₆)-alkyl; R² is hydrogen, (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, (C₁-C₆)-alkyl substituted by halogen, (C₁-C₆)-alkylsubstituted by hydroxy, (CH₂)_(n)—(C₃-C₇)-cycloalkyl optionallysubstituted by (C₁-C₆) -alkoxy or by halogen,CH(CH₃)—(C₃-C₇)-cycloalkyl, (CH₂)_(n+)—C(O)—R⁹, (CH₂)_(n+1)—CN,bicyclo[2.2.1]heptyl, (CH₂)_(n+1)—O—(C₁-C₆)-alkyl,(CH₂)_(n)-heterocycloalkyl, (CH₂)_(n)-aryl or (CH₂)_(n)-5 or 6-memberedhetaroaryl containing one, two or three heteroatoms selected from thegroup consisting of oxygen, sulphur or nitrogen wherein aryl,heterocycloalkyl and heteroaryl are unsubstituted or substituted by oneor more substituents selected from the group consisting of hydroxy,halogen, (C₁-C₆)-alkyl and (C₁-C₁)-alkoxy; R³, R⁴ and R⁶ are eachindependently hydrogen, hydroxy, halogen, (C₁-C₆)-alkyl, (C₁-C₆) -alkoxyor O—(C₃-C₆)-cycloalkyl; R⁵ is NO₂, CN, C(O)R⁹ or SO₂R¹⁰; R⁷ and R⁸ areeach independently hydrogen or (C₁-C₆)-alkyl; R⁹ is hydrogen,(C₁-C₆)-alkyl, (C₁-C₆)-alkoxy or NR⁷R⁸; R¹⁰ is (C₁-C₆)-alkyl optionallysubstituted by halogen, (CH₂)_(n)—(C₃-C₆)-cycloalkyl,(CH₂)_(n)—(C₃-C₆)-alkoxy, (CH₂)_(n)-heterocycloalkyl or NR⁷R⁸; n is 0,1, or 2; or a pharmaceutically acceptable acid addition salt thereof.